Hexahydro-pyrrolo-isoquinoline compounds

ABSTRACT

Certain hexahydro-pyrrolo-isoquinoline compounds are histamine H 3  receptor and serotonin transporter modulators useful in the treatment of histamine H 3  receptor- and serotonin-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119(e) of provisional application Serial No. 60/691,958, filed on Jun. 17, 2005, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are modulators of the histamine H₃ receptor and the serotonin transporter. More particularly, there is provided by the present invention hexahydro-pyrrolo-isoquinoline compounds and methods for using them to treat disorders and conditions mediated by the histamine H₃ receptor and the serotonin transporter. As a consequence of these activities the compounds of the present invention will have therapeutic utility for the treatment of depression and a range of related disorders.

BACKGROUND OF THE INVENTION

Depression is a chronic illness with an estimated lifetime prevalence of 17%. The total annual cost of depression in the USA is estimated at $44 billion. As such, it represents a major health problem with a serious pharmacoeconomic impact (Griffiths, R. I. et al. Pharmacoeconomics 1999, 15(5), 495-505). Although the biochemical basis of depression is not completely elucidated, the most commonly accepted hypothesis states that depression occurs when monoaminergic neurotransmission in the brain is impaired. This theory is largely based on the observation that compounds that improve noradrenergic and/or serotoninergic neurotransmission often have beneficial effects in depression. Such an improvement in monoaminergic neurotransmission can be achieved in several ways. The biological effect of noradrenaline is terminated by two mechanisms: reuptake from the synaptic cleft into the neuron via the norepinephrine transporter (NET), and degradation by monoamine oxidase (MAO). For serotonin, reuptake in the neuron via the serotonin transporter (SERT) likewise limits its availability in the synaptic cleft.

Currently, clinical treatment of depression relies mainly on four types of drugs: 1) MAO inhibitors; 2) tricyclic antidepressants (TCA); 3) selective serotonin reuptake inhibitors (SSRI); and 4) other drugs such as reboxetine and venlafaxine. MAOs have long been used as second-line drugs because of their potentially dangerous side effects, and more recently, reversible MAO-A selective inhibitors with improved profiles have been described (Bonnet, U. CNS Drug Rev. 2002, 8(3), 283-308). TCAs such as amitryptiline display complex pharmacological activities. They inhibit reuptake of noradrenaline and serotonin via their respective transporters, but also have affinity at muscarinic and histamine H₁ receptors. Thus, their efficacy in treating depression is counterbalanced by numerous unwanted side effects. The SSRIs, which represent the largest and most successful group of antidepressants, show a higher selectivity for the SERT than for the NET, although the exact affinity ratio varies from drug to drug. This class of drugs is characterized by a milder side-effect profile than the MAO-inhibitors or the TCAs. Other drugs have been described, such as reboxetine, which preferentially targets the NET, and venlafaxine, which has dual activity at the SERT and NET (Olver, J. S. et al. CNS Drugs 2001, 15(12), 941-954).

Although remarkable progress has been made in the treatment of depression, there remains opportunity for improvement. The delay between start of treatment and subjective improvement is a case in point. Most drugs do not cause an improvement in the Hamilton Rating Scale for Depression until after several weeks of treatment, potentially leaving the patient subject to severe mental anguish during this time. Currently available drugs have a limited response rate and in most clinical trials only about 30% of patients show clinical improvement (Menza, M. A. et al. J. Clin. Psych. 2000, 61(5), 378-381). Psychiatrists frequently have to evaluate several drugs for individual patients before a satisfactory therapeutic response is observed. Consequently there is a significant therapeutic need for drugs with a faster onset of action, improved side effect profiles and higher response ratio.

In order to appreciate the rationale for a combined SERT/H₃ antagonist, it is necessary to understand the physiology of the histamine H₃ receptor. This receptor was described in 1983 (Arrang, J.-M. et al. Nature (London) 1983, 302(5911), 832-837) as a presynaptic, auto-inhibitory receptor on histaminergic neurons with a characteristic pharmacology. Activation of the H₃ receptor was shown to decrease the amount of histamine released from the nerve terminals and to inhibit the activity of histidine decarboxylase, the rate-limiting enzyme in the synthesis of histamine. The cloning and characterization of the human H₃ receptor made it possible to explore its pharmacology (Lovenberg, T. W. et al. Molec. Pharmacol. 1999, 55(6), 1101-1107). It is now known that the H₃ receptor is expressed on a variety of neurons and thus, when activated, decreases the release of a number of other neurotransmitters including noradrenaline, dopamine, and acetylcholine (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3), 253-278). For the purpose of this discussion, we will focus on its known effects on the release of the neurotransmitters involved in depression, noradrenaline and serotonin. Although the serotoninergic cell bodies are found in the dorsal raphe nucleus while the histaminergic cells are located in the tuberomammillary nucleus of the hypothalamus, both systems have extensive projections throughout the brain. In several regions, such as the suprachiasmatic nucleus (Laitinen, K. S. M. et al. Eur. J. Pharmacol. 1995, 285(2), 159-164) and striatum both neurotransmitters are present. It is known that activation of the H₃ receptor leads to a decreased release of serotonin, for instance in rat cortex slices (Fink, K. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1990, 342(5), 513-519; Schlicker, E. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337(5), 588-590). Functional antagonists of the H₃ receptor lead to an increased release of noradrenaline in the central (mouse cortex slices, Leurs, R. et al. J. Pharmacol. Exp. Ther. 1996, 276(3), 1009-1015; the rat hippocampus, Alvez-Rodrigues, A. et al. Brain Res. 1998, 788(1-2), 179-186) and peripheral nervous system (human myocardial nerves, Hatta, E. et al. J. Pharmacol. Exp. Ther. 1997, 283(2), 494-500; guinea-pig intestinal sympathetic nerves, Blandizzi, C. et al. Br. J. Pharmacol. 2000, 129(7), 1387-1396). However, there is little evidence that H₃ receptor antagonists alone are capable of increasing serotonin levels in vivo to those required for antidepressant effects. Microdialysis studies of the effect of H₃ antagonists on serotonin levels in the brain of live animals are lacking. There are sparse reports indicating that thioperamide, an H₃ receptor antagonist, may have an antidepressant effect per se in the mouse or rat forced swim test (Lamberti, C. et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. et al. Psychopharmacology 1999, 142(2), 215-220).

The rationale for combining H₃ receptor blockade and SERT activity in one single molecule is the expectation that both mechanisms will contribute synergistically to enhanced concentrations of serotonin in the synaptic cleft. Antagonism at the H₃ receptor will provide increased release of serotonin-containing vesicles into the synaptic cleft, and concomitant blockade of the SERT will decrease the neuronal reuptake of these neurotransmitter molecules. Thus, higher concentrations of serotonin will be achieved, leading to an enhanced therapeutic effect.

Among the prominent vegetative symptoms of depression are disturbed sleep and the daytime fatigue associated with it. Polysomnographic investigations have shown severe disturbances in the sleep architecture of depressed patients. Among the typical abnormalities observed are: discontinuous sleep, decreased slow-wave sleep, shorter latency to REM sleep and an increased intensity and duration of REM sleep (Riemann, D. et al. Neuropsychobiology 2002, 45(Suppl. 1), 7-12). It is believed that suppression of REM sleep is involved in antidepressant efficacy. This is illustrated by the dramatic success of overnight deprivation of (REM) sleep (Riemann et al. 2002). Another non-pharmacological treatment for depression, electroconvulsant therapy, likewise decreases REM sleep. Virtually all of the available antidepressant drugs, regardless of their neurochemical mechanism of action, suppress REM sleep, nefazodone (a 5-HT_(2A) antagonist) being the exception (Sharpley, A. L., Cowen, P. J. Biol. Psych. 1995, 37(2), 85-98). Antidepressant drugs also affect slow-wave-sleep, although in a less clear manner. H₃ antagonists share this REM-sleep suppressing property and one of the main biological effects of histamine H₃ antagonists is to improve wakefulness. Administration of H₃ antagonists has been shown to decrease REM and non-REM sleep in several animal species. For example, the H₃ antagonist carboperamide induces waking in rats (Monti, J. M. et al. Neuropsychopharmacology 1996, 15(1), 31-35). Another H₃ antagonist, thioperamide, decreased both REM and non-REM sleep in rats (Monti, J. M. et al. Eur. J. Pharmacol. 1991, 205(3), 283-287) and cats (Lin, J.-S. et al. Brain Res. 1990, 523(2), 325-330). It is of interest to note that although H₃ antagonists promote wakefulness, they do so much less potently than amphetamine derivatives. They may thus be considered mild stimulants. The daytime correlate of disturbed sleep is fatigue. Indeed, fatigue and lethargy are prominent symptoms of depression, and there is considerable interest in the use of stimulants to augment antidepressant therapy (Menza et al., 2000). However, most of the available stimulants, like the amphetamine derivatives and methylphenidate, carry a considerable risk of abuse and are not ideal therapeutic choices. Modafinil, a wake-promoting compound of unknown mechanism with a lower addictive potential, is marketed for the treatment of narcolepsy. In a small series of patients it was shown that addition of a low dose of modafinil to traditional antidepressant therapy resulted in a faster onset of action. Fatigue was particularly responsive to this therapy, but the cognitive and physical subscales of the Hamilton Rating Scale for Depression also improved (Menza et al., 2000). The behavioral profile of H₃ antagonists (suppression of sleep with no stimulation of locomotor activity and limited addictive potential) is much like that of modafinil. Therefore, a combined H₃/SSRI compound would provide symptomatic relief for the fatigue during the first weeks of treatment, before the mood-elevating effect of the SSRI can be noticed.

Depression is also associated with a number of cognitive symptoms such as impaired memory and concentration difficulties. H₃ antagonists have been shown to improve memory in a variety of memory tests, including the elevated plus maze in mice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), a two-trial place recognition task (Orsetti, M. et al. Behav. Brain Res. 2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S. et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and the radial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10), 905-910). Also, in the spontaneously hypertensive rat, an animal model for the learning impairments in attention-deficit disorders, H₃ antagonists were shown to improve memory (Fox, G. B. et al. Behav. Brain Res. 2002, 131(1-2), 151-161). Although no human studies are available, the evidence indicates that a combined SERT/H₃ antagonist will provide additional benefit in combating the cognitive impairments associated with depression.

In summary, the combination of H₃ receptor antagonism with SERT activity will result in the production of drugs with an improved antidepressant profile compared to an SSRI alone. These drugs will be especially efficacious in ameliorating the symptoms of fatigue, disturbed sleep and memory loss associated with depression.

The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety.

References cited herein, including U.S. Patent Appl. No. 60/637173, U.S. patent application Ser. No. 11/300880, and U.S. Provisional Appl. No. 60/692003, are incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The invention features a compound of formula (I):

wherein n is 0 or 1; m is 0, 1, or 2; R² and R³ are independently selected from —H, or from the group consisting of:

-   -   A) —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl, —C₃₋₇cycloalkyl,         —C₁₋₆alkylC₃₋₇cycloalkyl, benzyl;     -   B) phenyl or pyridyl, optionally fused at two adjacent carbon         ring members to a three- or four-membered hydrocarbon moiety to         form a fused five- or six-membered aromatic ring, which moiety         has one carbon atom replaced by >O, >S, >NH, or >N(C₁₋₄alkyl),         and which moiety has up to one additional carbon atom optionally         replaced by —N═;     -   C) a 4-8 membered heterocyclic ring, said heterocyclic ring         having a carbon atom which is the point of attachment, having 1         or 2 heteroatom members selected from >O, >S(O)₀₋₂, and >NH, and         having 0 or 1 double bonds; and     -   D) a monocyclic aromatic hydrocarbon group having five or six         ring atoms, having a carbon atom which is the point of         attachment, having one carbon atom replaced by >O, >S, >NH, or         >N(C₁₋₄alkyl), having up to one additional carbon atom         optionally replaced by —N═, and optionally benzofused or         pyridofused;     -   where each of A)-D) is optionally mono-, di-, or tri-substituted         with a moiety selected from the group consisting of —OH,         —C₁₋₄alkylOH, —OC₁₋₆alkyl, —CN, —NO₂, —N(R^(d))R^(e) (wherein         R^(d) and R^(e) are independently —H or —C₁₋₆alkyl),         —C(O)N(R^(d))R^(e), —N(R^(d))C(O)R^(d), —N(R^(d))SO₂C₁₋₆alkyl,         —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(d))R^(e), —SCF₃,         halo, —CF₃, —OCF₃, —COOH, —COOC₁₋₆alkyl, —OC(O)N(R^(d))R^(e),         and —OC(O)OR^(d);     -   or, alternatively,     -   R² and R³ may be taken together with the nitrogen to which they         are attached to form a 4-8 membered heterocyclic ring, said         heterocyclic ring having 0 or 1 additional heteroatom members         separated from the nitrogen of attachment by at least one carbon         member and selected from >O, >S(O)₀₋₂, >NH, and >NR^(f), having         0 or 1 double bonds, having 0, 1, or 2 carbon members separated         from the nitrogen of attachment by at least one carbon member         which is a carbonyl, optionally benzo or pyrido fused,         optionally having one carbon member that forms a bridge, and         having 0-5 carbon member substituents R^(ff),         -   R^(f) is selected from the group consisting of —C₁₋₆alkyl             optionally mono-, di-, or tri-substituted with halo,             —C₃₋₆alkenyl, —C₃₋₆alkynyl, —C₃₋₇cycloalkyl,             —C₁₋₆alkylC₃₋₇cycloalkyl, —C₂₋₆alkylOH, —C(O)N(R^(g))R^(h)             (wherein R^(g) and R^(h) are independently —H or             —C₁₋₈alkyl), —C(O)R^(i) (where R^(i) is —C₁₋₆alkyl,             —C₃₋₈cycloalkyl, phenyl, or 5- or 6-membered aromatic             heterocyclyl, each optionally mono-, di-, or tri-substituted             with —C₁₋₃alkyl, —OH, —OC₁₋₆alkyl, —CF₃, or halo),             —S(O)₀₋₂—C₁₋₆alkyl, and —COOC₁₋₆alkyl;         -   R^(ff) is selected from the group consisting of —C₁₋₆alkyl             optionally mono-, di-, or tri-substituted with halo,             —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl,             —C₁₋₆alkylC₃₋₇cycloalkyl, halo, —OH, —C₁₋₆alkylOH,             —OC₁₋₆alkyl, —OC₂₋₃alkylO—, —CN, —NO₂, —N(R^(g))R^(h)             (wherein R^(g) and R^(h) are independently —H or             —C₁₋₆alkyl), —C(O)N(R^(g))R^(h), —N(R^(g))C(O)R^(g),             —N(R^(g))SO₂C₁₋₆alkyl, —C(O)R^(i) (where R^(i) is             —C₁₋₆alkyl, —C₃₋₈cycloalkyl, phenyl, or 5- or 6-membered             aromatic heterocyclyl, each optionally mono-, di-, or             tri-substituted with —C₁₋₃alkyl, —OH, —OC₁₋₆alkyl, —CF₃, or             halo), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(y))R^(z), —SCF₃, —OCF₃,             —COOH, and —COOC₁₋₆alkyl;     -   R⁴ is —OH, —OC₁₋₆alkyl, —CF₃, —C₁₋₆alkyl, or halo; two R⁴         substituents may be taken together to form methylene or         ethylene; or one of R⁴ is taken together with R² to form         methylene, ethylene, or propylene; wherein each methylene,         ethylene, or propylene is optionally substituted with —OH,         —OC₁₋₆alkyl, —SC₁₋₆alkyl, —CF₃, —C₁₋₆alkyl, amino, or halo;     -   R⁵ is selected from the group consisting of —H, —C₁₋₆alkyl, —OH,         —OC₁₋₆alkyl, —SC₁₋₆alkyl, and halo;     -   Ar¹ is an aryl or heteroaryl ring selected from the group         consisting of:         -   a) phenyl, optionally mono-, di-, or tri-substituted with             R^(j) or di-substituted on adjacent carbons with             —OC₁₋₄alkyleneO— optionally mono- or di-substituted with             fluoro, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,             —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;         -   R^(j) is selected from the group consisting of             -   1) —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl optionally mono-, di-,                 or tri-substituted with halo, —C₂₋₆alkenyl,                 —OC₃₋₆alkenyl, —C₂₋₆alkynyl, —OC₃₋₆alkynyl,                 —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,                 —N(R^(k))R^(l) (wherein R^(k) and R^(l) are                 independently —H or —C₁₋₆alkyl), —N(R^(k))COR^(l),                 —N(R^(k))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,                 —S(O)₀₋₂—C₁₋₆alkyl, —C(O)N(R^(m))R^(n) (wherein R^(m)                 and R^(n) are independently —H or —C₁₋₆alkyl, or R^(m)                 and R^(n) taken together with their nitrogen of                 attachment form a 4-8 membered heterocyclic ring having                 1 or 2 heteroatom members selected from >O,                 >S(O)₀₋₂, >NH, and >NC₁₋₆alkyl, having 0 or 1 double                 bonds, having 0 or 1 carbonyl members),                 —SO₂N(R^(m))R^(n), —SCF₃, halo, —CF₃, —COOH,                 —COOC₁₋₆alkyl, and —COOC₃₋₇cycloalkyl; and             -   2) a 4-8 membered saturated or partially saturated                 heterocyclic ring, having 1 or 2 heteroatom members                 selected from >O, >S(O)₀₋₂, >NH, and >NC₁₋₆alkyl, having                 0 or 1 carbonyl members; said ring optionally mono-,                 di-, or tri-substituted with R^(p);                 -   R^(p) is a substituent independently selected from                     the group consisting of: —OH, —C₁₋₆alkyl,                     —OC₁₋₆alkyl, phenyl, —CN, —NO₂, —N(R^(q))R^(r)                     (wherein R^(q) and R^(r) are independently —H,                     —C₁₋₆alkyl, or —C₂₋₆alkenyl), —C(O)N(R^(q))R^(r),                     —N(R^(q))C(O)R^(r), —N(R^(q))SO₂C₁₋₆alkyl,                     —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,                     —SO₂N(R^(q))R^(r), —SCF₃, halo, —CF₃, —OCF₃, —OCHF₂,                     —COOH, and —COOC₁₋₆alkyl;         -   b) phenyl or pyridyl fused at two adjacent carbon ring             members to a three membered hydrocarbon moiety to form a             fused five membered aromatic ring, which moiety has one             carbon atom replaced by >O, >S, >NH, or >N(C₁₋₄alkyl) and             which moiety has up to one additional carbon atom optionally             replaced by —N═, the fused rings optionally mono-, di-, or             tri-substituted with R^(t);             -   R^(t) is a substituent independently selected from the                 group consisting of: —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl,                 phenyl, —CN, —NO₂, —N(R^(u))R^(v) (wherein R^(u) and                 R^(v) are independently —H or —C₁₋₆alkyl),                 —C(O)N(R^(u))R^(v), —N(R^(u))C(O)R^(v),                 —N(R^(u))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,                 —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(u))R^(v), —SCF₃, halo,                 —CF₃, —OCF₃, —OCHF₂, —COOH, and —COOC₁₋₆alkyl;         -   c) phenyl fused at two adjacent ring members to a four             membered hydrocarbon moiety to form a fused six membered             aromatic ring, which moiety has 0, 1, or 2 carbon atoms             replaced by —N═, the fused rings optionally mono-, di-, or             tri-substituted with R^(t);         -   d) a monocyclic aromatic hydrocarbon group having five ring             atoms, having a carbon atom which is the point of             attachment, having one carbon atom replaced by >O, >S, >NH,             or >N(C₁₋₄alkyl), having up to one additional carbon atom             optionally replaced by —N═, optionally mono- or             di-substituted with R^(t), and optionally benzofused or             pyridofused at two adjacent carbon atoms, where the             benzofused or pyridofused moiety is optionally mono-, di-,             or tri-substituted with R^(t); and         -   e) a monocyclic aromatic hydrocarbon group having six ring             atoms, having a carbon atom which is the point of             attachment, having one or two carbon atoms replaced by —N═,             optionally mono- or di-substituted with R^(t), and             optionally benzofused or pyridofused at two adjacent carbon             atoms, where the benzofused or pyridofused moiety is             optionally mono- or di-substituted with R^(t);     -   and enantiomers, diastereomers, hydrates, solvates thereof, and         pharmaceutically acceptable salts, esters, and amides thereof.

The invention also features a compound of formulae (II) or (III):

wherein

-   -   R², R³, R⁵, and Ar¹ are as defined for formula (I);     -   and enantiomers, diastereomers, hydrates, solvates thereof, and         pharmaceutically acceptable salts, esters, and amides thereof.

Isomeric forms of the compounds of formulae (I), (II), and (III), and of their pharmaceutically acceptable salts, esters, and amides, are encompassed within the present invention, and reference herein to one of such isomeric forms is meant to refer to at least one of such isomeric forms. One of ordinary skill in the art will recognize that compounds according to this invention may exist, for example in a single isomeric form whereas other compounds may exist in the form of a regioisomeric mixture.

The invention also features pharmaceutical compositions containing such compounds and methods of using such compounds and compositions in the treatment or prevention of disease states mediated by the histamine H₃ receptor and the serotonin transporter.

Compounds of the present invention are useful in combination with other therapeutic agents as a combination therapy method, including use in combination with H₁ receptor antagonists, H₂ receptor antagonists, H₃ receptor antagonists, and neurotransmitter modulators such as serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors, and modafinil.

Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the results of measuring levels of serotonin and dopamine in the cortex of freely moving rats after subcutaneous injection of 1 mg/kg of Example 8A.

DETAILED DESCRIPTION

Particular preferred compounds of the invention comprise a compound of formula (I), or an enantiomer, diastereomer, hydrate, solvate thereof, or a pharmaceutically acceptable salt, amide or ester thereof, wherein n, m, R²⁻⁵, and Ar¹ have any of the meanings defined hereinabove and equivalents thereof, or at least one of the following assignments and equivalents thereof. Such assignments may be used where appropriate with any of the definitions, claims or embodiments defined herein:

Preferably, n is 0 or 1.

Preferably, m is 0.

Preferably, R² and R³ are independently selected from —H, or optionally substituted, from the group consisting of:

-   A) methyl, ethyl, isopropyl, butyl, pentyl, hexyl, allyl, propargyl,     cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,     benzyl, -   B) phenyl, pyridyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or     7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or     7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or     7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,     imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5,     6 or 7-yl, 1 H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,     1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5     or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, -   C) azetidinyl, pyrrolidinyl, piperidinyl, and -   D) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,     1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl,     thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl,     1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2-     or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or 3-indolyl,     2-benzthiazolyl, 2-benzimidazolyl, and 3-indazolyl.

More preferably, R² and R³, optionally substituted, are independently selected from methyl, ethyl, isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and methoxyethyl.

Even more preferably, R² and R³ are, independently, ethyl, isopropyl, methoxyethyl, or 2-benzothiazolyl.

In a preferred embodiment, R² and R³, optionally substituted, are taken together with the nitrogen to which they are attached to form a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1,3-dihydro-isoindo1-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and 1,1-dioxo-1λ⁶-thiomorpholin-4-yl.

Preferably, R² and R³ are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring selected from piperidine, pyrrolidine, and morpholine, said ring substituted with 1 or 2 substituents R^(ff).

Preferably, R^(ff) is selected from the group consisting of methyl, ethyl, isopropyl, butyl, hexyl, —CF₃, —CHF₂, vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo, —OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy, pentyloxy, —O(CH₂)₂O—, —O(CH₂)₃O—, —CN, amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl, methanesulfanyl, methanesulfonyl, methanesulfonamido, —C(O)R^(i), —COOH, and ethoxycarbonyl.

More preferably, R^(ff) is selected from the group consisting of methyl, fluoro, —OH, —CF₃, hydroxymethyl, hydroxyethyl, dimethylamino, ethoxycarbonyl, and —O(CH₂)₂O—.

Preferably, R^(i) is selected from the group consisting of methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl, N-methylpyrrolyl, and 1-methylimidazolyl.

More preferably, R² and R³ are taken together with the nitrogen to which they are attached to form azetidinyl, 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl, 4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl, 4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl, 4-hydroxyethyl piperidinyl, 3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl, or 2-methylmorpholin-4-yl.

Even more preferably, R² and R³ are taken together with the nitrogen to which they are attached to form 4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.

Preferably, R⁴ is methoxy, ethoxy, isopropoxy, pentyloxy, —CF₃, methyl, ethyl, propyl, isobutyl, pentyl, chloro, or fluoro.

More preferably, R⁴ is hydroxy, methyl, methoxy, fluoro, or —CF₃.

Preferably, two R⁴ are taken together to form methylene.

Preferably, R² and one of R⁴ are taken together form methylene, ethylene, or propylene, each optionally substituted with —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —CF₃, —C₁₋₆alkyl, amino, or halo.

More preferably, R² and one of R⁴ are taken together form methylene or ethylene.

Preferably, R⁵ is hydrogen, methyl, ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylsulfanyl, bromo, chloro, fluoro, or iodo.

More preferably, R⁵ is hydrogen.

Preferably, Ar¹, optionally substituted, is selected from the group consisting of:

a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4, 5, 6 or 7-yl, 1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,

b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl, imidazo[1,2-a]pyridin-5, 6, 7 or 8-yl, pyrazolo[1,5-a]pyridin-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,

c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,

d) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl, and

e) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6], [2,7], [2,8]naphthyridin-1-, 3-, or 4-yl.

More preferably, Ar¹, optionally substituted, is selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thiophenyl.

Even more preferably, Ar¹ is selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 4-methanesulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl, thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl, 2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl, 2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl, 4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl, 1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.

In a particular embodiment, Ar¹, optionally substituted with halo, is 4-methoxyphenyl or 4-methanesulfanylphenyl.

Preferably, Ar¹ is cis to the pyrrolidine ring of formula (I).

Preferably, the R³R²N-containing ether substituent of formula (I) is at the 9-position.

With respect to compounds of formulae (II) and (III), preferably, R² and R³ are taken together with the nitrogen to which they are attached to form piperidinyl, 4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.

Preferably, Ar¹ is 4-methoxyphenyl or 4-methylsulfanylphenyl.

Preferably, R⁵ is —H.

It is understood that some compounds referred to herein are chiral and/or have diastereomeric or geometric isomeric centers, for example cis- and trans-isomers. The present invention encompasses all such isomers, including optical isomers, such as stereoisomers and racemic mixtures, diastereomers, regioisomers, and geometric isomers that possess the activity that characterizes the compounds of this invention. Compounds of the invention may exist as single enantiomers, mixtures of enantiomers, or racemic mixtures. In certain embodiments, the absolute configuration of a single enantiomer may be unknown. Compounds of the invention may exist as a single diastereomers, or as a mixture of diastereomers. In addition, certain compounds referred to herein can exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all such solvated and unsolvated forms that possess the activity that characterizes the compounds of this invention.

Compounds according to the present invention that have been modified to be detectable by some analytic technique are also within the scope of this invention. The compounds of the present invention may be labeled with radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, and the like for use in imaging or for radioactive treatment of patients. An example of such compounds is an isotopically labeled compound, such as an ¹⁸F isotopically labeled compound that may be used as a probe in detection and/or imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Preferably, compounds of the present invention labeled with ¹⁸F or ¹¹C may be used as a positron emission tomography (PET) molecular probe for studying disorders mediated by the histamine H₃ receptor and the serotonin transporter. Another example of such compounds is an isotopically labeled compound, such as a deuterium and/or tritium labeled compound that may be used in reaction kinetic studies. The compounds described herein may be reacted with appropriate functionalized radioactive reagents using conventional chemistry to provide radiolabeled compounds.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with a compound of formulae (I), (II), or (III), or with a compound that converts to a compound of formulae (I), (II), or (III) in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.

Preferred compounds, which are hexahydro-pyrrolo-isoquinoline compounds, are selected from the group consisting of:

EX CHEMICAL NAME  1A Cis-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1a]isoquinoline;  1B Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1a]isoquinoline;  1C Trans-6-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1a]isoquinoline;  2A Cis-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  2B Trans-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  2C Trans-6-(4-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  3 Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenylamine;  4A Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  4B Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  4C Cis-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  4D Trans-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  5A Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline;  5B Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline;  5C Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline;  6A Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  6B Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  6C Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  7A Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  7B Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  7C Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  8A Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  8B 1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  8C 1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  8D Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  8E Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline;  8F Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;  9A Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenol;  9B Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 10A Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 10B Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 10C Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 11A Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 11B Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 11C Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 12A Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 12B Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 12C Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 12D Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 13A Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 13B Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 14A Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 14B Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 14C Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 15 Cis-3-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 16 Cis-2-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 17 Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 18 Cis-6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 19 Cis-6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 20 Cis-6-(2,5-dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 21 Cis-6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 22 Cis-6-(3,4,5-Trimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 23 Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 24A Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 24B Trans-9-(3-piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 25 Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 26 Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 27A Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 27B Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 28 Cis-7-(1-Isopropyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-2-methyl- 1,2,3,4-tetrahydro-isoquinoline; 29 Cis-9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 30 Cis-Dimethyl-{4-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-phenyl}-amine; 31 Cis-9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 32 Cis-6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 33 Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 34 Cis-6-(3-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 35A Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 35B Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 36 Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trimethylsilanylethynyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 37 Cis-6-(4-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 38 Cis-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 39A Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 39B Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 39C 6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 40 Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 41A Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 41B Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 42 Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 43 Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 44 Trans-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 45 Cis-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 46 Cis-6-(4-Methoxy-phenyl)-9-[3-(3S-methyl-morpholin-4-yl)-propoxy]- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 47 Cis-9-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-6-(4-methoxy-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 48A Cis-6-(4-imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 48B Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 49 Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 50A Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 50B Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 51A Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; 51B Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; 52 Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 53 Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 54 Cis-9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 55 Cis-6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 56 Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 57 Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 58 Cis-3-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 59 Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 60 Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 61 Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 62 Cis-9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 63 Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 64 Cis-6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 65 Cis-6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 66A Cis-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 66B Trans-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 67 Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trifluoromethyl-phenyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 68 6-Biphenyl-4-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 69 9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-2-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 70 9-(3-Morpholin-4-yl-propoxy)-6-quinolin-7-yl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 71 6-(1H-Indol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 72 6-(1H-Benzoimidazol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 73 6-(1H-Benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 74 6-(1-Methyl-1H-benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 75 9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-1-yl-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 76 6-Benzo[b]thiophen-7-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 77 6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 78 Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine; 79 6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 80 9-(3-Morpholin-4-yl-propoxy)-6-oxazol-5-yl-1,2,3,5,6,10b-hexahydro- pyrrolo[2,1-a]isoquinoline; 81 6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 82 6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 83 6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 84 6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 85 6-(3-Chloro-4-difluoromethoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 86 (4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1- a]isoquinolin-9-yloxy]-propyl}-morpholin-2-yl)-methanol; 87 (4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1- a]isoquinolin-9-yloxy]-propyl}-morpholin-3-yl)-methanol; 88 6-(3,5-Bis-trifluoromethyl-phenyl)-9-(3-piperidin-1-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 89 (1R,6S)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 90 (1S,6R)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 91 (1S,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 92 (1R,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 93 Trans-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 94 (1R,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 95 (1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 96A Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b- hexahydro-pyrrolo[2,1-a]isoquinoline; 96B Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 97A Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 97B Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 98A Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; and 98B Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)- 1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline.

The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety. Where chemical symbols are used, it is understood that they are read from left to right, and that otherwise their spatial orientation has no significance.

The compounds as described above may be made according to processes within the skill of the art and/or that are described in the schemes and examples that follow. To obtain the various compounds herein, starting materials may be employed that carry the ultimately desired substituents though the reaction scheme with or without protection as appropriate. This may be achieved by means of conventional protecting groups, such as those described in “Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd) ed., John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Alternatively, it may be necessary to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Such compounds, precursors, or prodrugs are also within the scope of the invention. Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent.

The hexahydro-pyrrolo-isoquinoline compounds of formulae (I), (II), and (III) may be prepared by a number of reaction schemes. Access to compounds of formula (I) is described in Schemes A-C. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme as compared to the other. In addition, synthetic sequences described in U.S. Pat. Appl. No. 60/637173 are incorporated by reference and may be applied to the preparation of compounds of formula (I).

Referring to Scheme A, methyl 3-hydroxybenzoate derivatives A1 may be alkylated with reagents A2, where Y is Cl, OH, a protected alcohol, or NR²R³, to form ethers A3. Where X is a suitable leaving group, such as Br, I, or OTs, alkylations may be performed by Williamson ether synthesis, using a suitable base such as K₂CO₃, Na₂CO₃, or NaH, in a solvent such as acetonitrile, with or without catalytic Kl or NaI. Alternatively, where X is OH, and Y is a protected hydroxyl or NR²R³, ethers of formula A3 may be prepared under Mitsunobu conditions. Where Y is Cl, ethers A3 may be converted to the corresponding amines (where Y is NR²R³) using standard methods. Alternatively, where Y is OH or protected hydroxyl, the amine group NR²R³ may be installed at a later stage in the synthesis.

Esters of formula A3 are condensed with N-vinylpyrrolidin-2-one to form imines of formula A5, which are subsequently reduced, preferably with LiAlH₄, to pyrrolidines A6.

Referring to Scheme B, alkylation of pyrrolidines A6 with alpha-haloketones B1 to form ketones B2 is accomplished in the presence of a tertiary amine base such as Et₃N or iPr₂NEt, in a suitable solvent such as THF or CH₂Cl₂. Cyclization to form tetrahydroisoquinolinium salts B3 is effected by exposure to a suitable protic or Lewis acid, such as methanesulfonic acid (MSA), trifluoroacetic acid, AlCl₃, TiCl₄, or BF₃.OEt₂ with or without a solvent such as CH₂Cl₂. Preferred conditions are neat MSA or MSA in CH₂Cl₂. The intermediate salts B3 may be reduced using standard reducing agents such as NaCNBH₃ in an acidic methanol medium to form tricyclic amines B6.

Alternatively, pyrrolidines A6 may be reacted with styrene oxides B4 to form alcohols B5. Ketones B2 may also be reduced by known methods, including NaBH₄, to the corresponding alcohols B5. Treatment of the intermediate alcohols B5 with MSA in CH₂Cl₂ provides cyclic species B6 directly. Where the OR group has been left as OH, the amino side chain may be installed at this stage using methods described above or methods known in the art. Alternatively, the OR group may be carried through the sequence as a suitably substituted 3-hydroxypropyloxy or 4-hydroxybutyloxy group (protected or unprotected as appropriate), and the terminal hydroxyl group may be converted to the desired amine functionality at an appropriate point during the synthetic sequence using standard methods such as those described above.

In another embodiment, pyrrolidines A6 may be coupled with mandelic acid derivatives B7 to form amides B8. Cyclization to form tricyclic amides B9 is performed as described above. Reduction of the carbonyl to provide compounds of formula B6 is accomplished with a reducing agent such as BH₃, in a solvent such as THF.

Although Scheme B is depicted to produce regioisomers B6 in which the OR substituent is at the 9-position of the tricyclic ring system, those skilled in the art will recognize that cyclization of compounds of formula B2, B5, and B8 may also provide regioisomers where the OR substituent is in the 7-position. Such regioisomers may be converted to compounds of formula (I) according to the procedures described above.

Compounds of formula C8, where OR is defined as in Scheme B, are alternatively prepared according to Scheme C. Intermediates of formula C1 may be commercially available or may be prepared by a variety of methods. Those skilled in the art will recognize that the amine side chain of compounds of formula (I) may be installed at an appropriate point during the sequence using standard methods including those described in Schemes A and B. If required, a protected amino group or surrogate may be used and later transformed into the amino group —NR²R³.

Formation of the aryl Grignard reagent, followed by reaction with malonic ester analogs C2, hydrolysis of the resulting diester, and decarboxylation provide acids of formula C3. Hydrolysis may be performed using methods known to one skilled in the art, including KOH in EtOH. Decarboxylation is typically accomplished through the application of heat. Curtius rearrangement, preferably using Et₃N and diphenylphosphoryl azide in a suitable solvent, installs a protected amine functionality. Where the solvent is t-BuOH, a Boc protecting group results. The protecting group may be subsequently removed under standard conditions, such as TFA in DCM, to form amines of formula C5.

Alternatively, halogen-metal exchange of the aryl bromides C1, followed by reaction with nitroalkenes C4, and subsequent reduction of the nitro group will provide amines of formula C5 directly. Reduction of the nitro group is accomplished using procedures well-known to those skilled in the art. Reaction of amines C5 with succinic anhydride, followed by ring closure, gives rise to the corresponding succinimides (structure not shown). The ring closure may preferably be accomplished using acetyl chloride, with or without the application of heat. Succinimides C6 are then reduced to hemiaminals C6 using a suitable reducing agent, such as NaBH₄, in a solvent such as dioxane.

Reaction under acidic conditions, such as MSA, leads to formation of the tricyclic system of compounds of formula C7. The lactam ring may be reduced to form compounds of formula C8 using a suitable reducing agent, such as BH₃, in a solvent such as THF. Where OR is OMe, the methyl protecting group may be removed at the C7 or C8 stage and replaced by the amine-containing side chain described in formula (I).

Compounds of formulae (II) and (III) are prepared according to procedures described above and those described in U.S. patent application Ser. No. 11/300880 and U.S. Patent Appl. No. 60/692003, as well as those described in the Examples below.

Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, or as racemic mixtures or mixtures of enantiomers, diastereomers, or regioisomers. Where regioisomeric or diastereomeric mixtures are obtained, isomers may be separated using conventional methods such as chromatography or crystallization. Where racemic (1:1) and non-racemic (not 1:1) mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art. Particularly useful separation methods may include chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

For therapeutic use, salts of the compounds of the present invention are those that are pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

Pharmaceutically acceptable salts, esters, and amides of compounds according to the present invention refer to those salt, ester, and amide forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which would favorably affect the pharmacokinetic properties of said compounds of the present invention. Those compounds having favorable pharmacokinetic properties would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which possess such pharmacokinetic properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.

Examples of acids that may be used in the preparation of pharmaceutically acceptable salts include the following: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Compounds of the present invention containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts; the alkali and earth alkaline metal salts (e.g. lithium, sodium, potassium, magnesium, calcium salts, which may be prepared by treatment with, for example, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide); and amine salts made with organic bases (e.g. primary, secondary and tertiary aliphatic and aromatic amines such as L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g., S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference.

Pharmaceutically acceptable esters and amides are those that are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines.

Representative pharmaceutically acceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, substituted phenyl, and phenylC₁₋₆alkyl-esters. Preferred esters include methyl esters. Furthermore, examples of suitable esters include such esters where one or more carboxyl substituents is replaced with p-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxy-carbonyl, 9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl, benzoyl methoxy-carbonyl, p-nitrobenzyloxy-carbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl, 2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, or tetrahydropyran-2-yloxycarbonyl.

The compounds of the present invention are modulators of the histamine H₃ receptor and of the serotonin transporter, and as such, the compounds are useful in the treatment of histamine H₃ and serotonin-mediated disease states. Compounds of the present invention possess serotonin transporter and H₃ receptor modulating activity. As such modulators, the compounds may act as antagonists or agonists. The effect of an antagonist may also be produced by an inverse agonist.

The compounds of the present invention are useful in methods for treating or preventing neurologic or CNS disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia, jet lag, and disturbed sleep), attention deficit hyperactivity disorders (ADHD), attention-deficit disorders, learning and memory disorders, learning impairment, memory impairment, memory loss, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS), circadian rhythym disorders, sleep/fatigue disorders, fatigue, drowsiness associated with sleep apnea, sleep impairment due to perimenopausal hormonal shifts, Parkinson's-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, work-related fatigue, lethargy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression. Said methods comprise the step of administering to a mammal suffering therefrom an effective amount of at least one compound of the present invention.

Particularly, as modulators of the histamine H₃ receptor and the serotonin transporter, the compounds of the present invention may be used in the treatment or prevention of depression, disturbed sleep, fatigue, lethargy, cognitive impairment, memory impairment, memory loss, learning impairment, and attention-deficit disorders.

The present invention also contemplates a method of treating or preventing a disease or condition mediated by the histamine H₃ receptor and the serotonin transporter with a combination therapy, comprising administering at least one compound of the present invention in combination with one or more therapeutic agents. Suitable therapeutic agents include: H₁ receptor antagonists, H₂ receptor antagonists, H₃ receptor antagonists, and neurotransmitter modulators such as serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors, and modafinil. In a particular embodiment, a combination therapy method includes administering at least one compound of present invention and administering modafinil, for example, for the treatment of narcolepsy, excessive daytime sleepiness (EDS), Alzheimer's disease, depression, attention-deficit disorders, MS-related fatigue, post-anesthesia grogginess, cognitive impairment, schizophrenia, spasticity associated with cerebral palsy, age-related memory decline, idiopathic somnolence, or jet-lag.

The present invention also contemplates a method for the treatment or prevention of a disease selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive impairment, memory impairment, memory loss, learning impairment, and attention-deficit disorders in mammals, comprising the step of administering to a mammal suffering therefrom an effective amount of a compound having both H₃ receptor modulating activity and serotonin transporter modulating activity. Preferably, said compound has an H₃ receptor binding activity of at least 20 nM in the human H₃ binding assay. Preferably, said compound has a serotonin transporter binding activity of at least 20 nM in the human SERT binding assay. Preferably, the ratio of the H₃ receptor binding activity in the human H₃ binding assay and the serotonin transporter binding activity in the human SERT binding assay for said compound is between 10:1 and 1:10.

Compounds of the present invention may be administered in pharmaceutical compositions to treat patients (humans and other mammals) with disorders mediated by the H₃ receptor and serotonin transporter. Thus, the invention features pharmaceutical compositions containing at least one compound of the present invention and a pharmaceutically acceptable carrier. A composition of the invention may further include at least one other therapeutic agent (for example, a combination formulation or combination of differently formulated active agents for use in a combination therapy method).

The present invention also features methods of using or preparing or formulating such pharmaceutical compositions. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes, or by inhalation. Preparations may also be designed to give slow release of the active ingredient. The preparation may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, compounds may be administered by intravenous infusion or topical administration, but more preferably by oral administration.

For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Compositions of such liquid may contain pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like); non-aqueous vehicles, which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oral routes. The compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Another mode of administration of the compounds of the invention may utilize a patch formulation to affect transdermal delivery. The compounds of this invention may also be administered by inhalation, via the nasal or oral routes using a spray formulation consisting of the compound of the invention and a suitable carrier.

Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the pharmaceutical compositions or the drug combinations of the present invention, whether or not formulated in the same composition. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration, and the weight of the patient. For therapeutic purposes, “effective dose” or “effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term “effective dose” or “effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor, or other clinician, the delaying of which disorder is mediated, at least in part, by the modulation of the histamine H₃ receptor and/or the serotonin transporter. Thus, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more drugs are analogously possible. Methods of combination therapy include co-administration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; and administration of two or more active agents separately formulated.

It is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, taken in 1 to 4 separate doses. Some compounds of the invention may be orally dosed in the range of about 0.05 to about 50 mg/kg daily, others may be dosed at 0.05 to about 20 mg/kg daily, while still others may be dosed at 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to 1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of about 0.1′)/0 to about 10% of drug to vehicle.

Examples

In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However, those methods are deemed to be within the scope of this invention.

Protocol for Preparative Reversed-Phase HPLC

-   Gilson® -   Column: YMC-Pack ODS-A, 5 μm, 75×30 mm -   Flow rate: 25 mL/min -   Detection: λ=220 & 254 nm -   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) -   1) 0.0 min 15% acetonitrile/85% water -   2) 20.0 min 99% acetonitrile/1% water

Protocol for HPLC (Reversed-Phase)

Method A:

-   Hewlett Packard Series 1100 -   Column: Agilent ZORBAX® Bonus RP, 5 μm, 4.6×250 mm -   Flow rate: 1 mL/min -   Detection: λ=220 & 254 nm -   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) -   1) 0.0 min 1% acetonitrile/99% water -   2) 20.0 min 99% acetonitrile/1% water -   Method B: -   Hewlett Packard HPLC -   Column: Agilent ZORBAX® Eclipse XDB-C8, 5 μm, 4.6×150 mm -   Flow rate: 1 mL/min -   Detection: λ=220 & 254 nm -   Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) -   1) 0.0 min 1% acetonitrile/99% water -   2) 8.0 min 99% acetonitrile/1% water -   3) 12.0 min 99% acetonitrile/1% water

Protocol for Preparative SFC

-   Thar Technologies® -   Column: Chiracel AD, 10 μm, 250×20 mm -   Flow rate: 37 gm/min -   Detection: λ=220 & 254 nm -   Mobile phase: Isocratic 30% IPA/70% CO₂ -   Pressure: 150 Bar -   Temperature: 35° C.

Protocol for Analytical SFC

-   Jasco® -   Column: Chiracel AD, 10 μm, 250×4.6 mm -   Flow rate: 1 gm/min -   Detection: λ=220 & 254 nm -   Mobile phase: Isocratic 30% IPA/70% CO₂ -   Pressure: 150 Bar -   Temperature: 35° C.

Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a 20 cm×4 cm concentrating zone.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), or DPX600 (600 MHz) spectrometer. The format of the ¹H NMR data below is: chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Normal phase flash column chromatography (FCC) was typically performed with RediSep® silica gel columns using 2 M ammonia in methanol/dichloromethane as eluent.

Chiral chromatography was performed using SFC HPLC (Chiralpak AD-h column), IPA/MeOH/CO₂, or by chiral HPLC (21×250 mm Chiracel AD-H, 5 μM (Chiral Technologies), 0.2% diethylamine in EtOH, 8 mL/min). Where a potential chiral center is designated with a solid bond (not bold or hashed), the structure is meant to refer to a racemic mixture, a mixture of enantiomers, or a single enantiomer as described. Where a single enantiomer is described without enantiomeric designation at the chiral center, it is understood that the absolute configuration of the single enantiomer is unknown.

Example 1-(A-C)

1A: Cis-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline

1B: Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline

1C: Trans-6-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline

Step 1. 3-(3-Chloro-propoxy)-benzoic acid methyl ester. A mixture of methyl 3-hydroxybenzoate (100.4 g, 0.657 mol), 1-bromo-3-chloropropane (78 mL, 0.789 mol), and K₂CO₃ (136.4 g, 0.986 mol) in acetone (430 mL) was heated to 60° C. for 42 h. The reaction mixture was cooled to 0° C. and then treated with diethyl ether (500 mL). The resultant mixture was filtered and concentrated to give a viscous oil. Short-path distillation (bp=134-136° C. at 1 torr) gave the product as colorless oil (138.85 g, 92%). ¹H NMR (acetone-d₆): 7.58 (dt, J=1.4, 7.7, 1H), 7.53 (dd, J=1.5, 2.6, 1H), 7.40 (t, J=8.0, 1H), 7.18 (ddd, J=0.9, 2.7, 8.3, 1H), 4.18 (t, J=5.9, 2H), 3.87 (s, 3H), 3.80 (t, J=6.5, 2H), 2.24 (quint, J=6.2, 2H).

Step 2. 3-(3-Iodo-propoxy)-benzoic acid methyl ester. A mixture of NaI (318.4 g, 2.12 mol) and 3-(3-chloro-propoxy)-benzoic acid methyl ester (138.5 g, 0.606 mol) in acetone (1.2 L) was heated to 60° C. for 2 d. The reaction mixture was concentrated and then diluted with CH₂Cl₂ (1 L) and water (500 mL). After mixing thoroughly, the layers were separated and the organic layer was washed with water (2×500 mL) and brine (1×200 mL), dried (MgSO₄), filtered and concentrated to give the desired product as a pale-yellow oil (190.95 g, 98%). The product was protected from light by wrapping the flask in aluminum foil. bp=154° C. at 1 torr. ¹H NMR (acetone-d₆): 7.61 (d, J=7.6, 1H), 7.56 (s, 1H), 7.44 (t, J=8.0, 1H), 7.23 (d, J=8.1, 1H), 4.16 (t, J=5.6, 2H), 3.89 (s, 3H), 3.48 (t, J=6.7, 2H), 2.31 (m, 2H).

Step 3. 3-(3-Piperidin-1-yl-propoxy)-benzoic acid methyl ester. A mixture of 3-(3-iodo-propoxy)-benzoic acid methyl ester (190.9 g, 0.596 mol), Na₂CO₃ (94.9 g, 0.894 mol), and piperidine (80 mL, 0.80 mol) in dry ethanol (400 mL) was protected from light with aluminum foil, and was heated to 60° C. under nitrogen for 22 h. The reaction mixture was diluted with CH₂Cl₂ (1 L), washed with water (4×600 mL) and brine (1×300 mL), dried (K₂CO₃), and concentrated to give the crude product as a biphasic (solid/liquid) mixture. Purification by Kugelrohr distillation (bp=215° C. at 1 torr) yielded a pale-yellow oil (143.4 g, 87%). MS (ESI): exact mass calcd for C₁₆H₂₃NO₃, 277.2; m/z found, 278.2 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.51 (d, J=7.6, 1H), 7.4 (m, 2H), 7.18 (m, 1H), 4.02 (t, J=6.4, 2H), 3.83 (s, 3H), 2.37 (t, J=7.0, 2H), 2.30 (br s, 4H), 1.84 (m, 2H), 1.46 (m, 4H), 1.35 (br m, 2H).

Step 4. 1-{3-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-propyl}-piperidine. To a 0° C. solution of NaH (95%, 17.4 g, 0.723 mol) in dry THF (500 mL) was added a solution of 3-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (143.2 g, 0.516 mol) and N-vinylpyrrolidin-2-one (66.0 mL, 0.620 mol) in dry THF (172 mL), via cannula, over the course of 18 min. The resultant mixture was stirred at 0° C. for 1 h (until gas evolution subsided) before heating to reflux for 5 h. The reaction mixture was then cooled to 0° C. and slowly treated with 12 N HCl (150 mL). The THF was removed in vacuo and an additional 12 N HCl (150 mL) and water (220 mL) was added and the mixture heated to 110° C. under nitrogen for 2 d. The reaction mixture was again cooled to 0° C. before slowly adding a solution of NaOH (150 g, 3.75 mol) in water (400 mL). The aqueous mixture was extracted with CH₂Cl₂ (2×500 mL). The combined extracts were washed with brine (1×500 mL), dried (Na₂CO₃), filtered and concentrated to give the crude product as a nearly black oil. Kugelrohr distillation of the crude product (bp=226-228° C. at 1 torr) yielded a pale-yellow oil (106.35 g, 72%). MS: exact mass calcd for C₁₈H₂₆N₂O, 286.2; m/z found, 287.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.37 (d, J=1.5, 1H), 7.32 (m, 2H), 7.00 (m, 1H), 3.96 (m, 4H), 2.95 (m, 2H), 2.49 (m, 6H), 1.99 (m, 4H), 1.59 (m, 4H), 1.45 (br m, 2H).

Step 5. 1-[3-(3-Pyrrolidin-2-yl-phenoxy)-propyl]-piperidine. To a 0° C. mixture of LiAlH₄ (14.28 g, 0.376 mol) in dry THF (200 mL) under nitrogen was added a solution of 1-{3-[3-(4,5-dihydro-3H-pyrrol-2-yl)-phenoxy]-propyl}-piperidine (106.4 g, 0.371 mol) in THF (200 mL) via cannula. Once addition was complete, the mixture was allowed to warm to room temperature (rt) and stir for 18 h. The mixture was then cooled to 0° C. and slowly treated with water (14.3 mL), followed by 15% aq. NaOH (14.3 mL), an additional 43 mL of water and 200 mL of THF. The resultant mixture was stirred for 2 h before filtering and concentrating to give a nearly colorless oil (94.4 g, 88%). MS: exact mass calcd for C₁₈H₂₈N₂O, 288.2; m/z found, 289.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.20 (t, J=7.8, 1H), 6.9 (d, J=7.8, 2H), 6.77 (dd, J=2.0, 8.2, 1H), 4.91 (s, 1H), 3.97 (m, 3H), 3.13 (m, 1H), 2.90 (m, 1H), 2.49 (m, 6H), 2.16 (m, 1H), 1.95 (m, 4H), 1.7 (m, 1H), 1.60 (m, 4H), 1.47 (br m, 2H).

Step 6. 1-Phenyl-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. A solution of 1-[3-(3-pyrrolidin-2-yl-phenoxy)-propyl]-piperidine (3.50 mmol) and styrene oxide (1.0 equiv.) in ethanol (0.5 molar) was heated at reflux until conversion was complete. The ethanol was removed in vacuo and the residue was then either passed through a plug of silica gel (NH₃ in MeOH/CH₂Cl₂) or taken on to the next step without purification to yield 1.12 g (79%) of the desired product as a mixture of diastereomers (colorless oil). MS: exact mass calcd for C₂₆H₃₆N₂O₂, 408.3; m/z found, 409.3 [M+H]⁺.

Step 7. A solution of 1-phenyl-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol (1.7 mmol) and MSA (5 mL/g of amino-alcohol) under nitrogen was stirred at rt. When the reaction was complete, the mixture was cooled to 0° C., diluted with 2 N NaOH and extracted with CH₂Cl₂. The organic extract was washed with brine, dried (Na₂CO₃), filtered and concentrated to give the crude products as a mixture of diastereomers. Purification by column chromatography (NH₃ in MeOH/CH₂Cl₂) followed by reverse-phase HPLC provided Examples 1 A-C in a combined yield of 41%.

1A: Cis-6-phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline. 18.4 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O, 390.3; m/z found, 391.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.28 (m, 2H), 7.24 (m, 1H), 7.13 (d, J=7.0, 2H), 6.76 (d, J=2.5, 1H), 6.67 (d, J=8.6, 1H), 6.58 (d, J=8.7, 1H), 4.74 4.25 (m, 1H), 3.97 (t, J=5.8, 2H), 3.72 (m, 1H), 3.45 (m, 3H), 3.17 (m, 2H), 2.83 (m, 2H), 2.73 (m, 1H), 2.15 (m, 6H), 1.83 (d, J=14.7, 2H), 1.67 (m, 3H), 1.40 (m, 1H).

1B: Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline. 299.0 mg (27%) as the TFA salt. MS: exact mass calcd exact mass calcd for C₂₆H₃₄N₂O, 390.3; m/z found, 391.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.37 (m, 2H), 7.31 (m, 1H), 7.17 (br s, 2H), 6.92 (br m, 3H), 5.10 (br s, 3H), 4.98 (br s, 1H), 4.52 (br s, 1H), 4.14 (t, J=5.6, 2H), 3.77 (br s, 2H), 3.65 (m, 2H), 3.49 (br s, 1H), 2.28 (m, 2H), 2.10 (br s, 2H), 1.96 (d, J=14.6, 2H), 1.90 (m, 3H), 1.54 (m, 1H).

1C: Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1a]isoquinoline. 129.8 mg (12%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O, 390.3; m/z found, 391.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.38 (m, 4H), 7.10 (d, J=7.3, 2H), 7.01 (d, J=7.8, 1H), 6.97 (d, J=8.2, 1H), 5.00 (s, 4H), 4.76 (m, 2H), 4.11 (d, J=4.6, 1 H), 3.7 (m, 4H), 3.30 (m, 3H), 2.75 (br m, 1H), 2.60 (m, 3H), 2.45 (m, 1 H), 2.23 (m, 3H), 2.05 (br m, 1 H), 1.75 (m, 5H), 1.45 (m, 1H).

Example 2-(A-C)

2A: Cis-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

2B: Trans-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

2C: Trans-6-(4-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Nitrophenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale, to yield 1.57 g (quant.) of the desired product as a mixture of diastereomers (yellow oil). MS: exact mass calcd for C₂₆H₃₆N₃O₄, 453.3; m/z found, 454.2 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 3.47 mmol scale, to give a 3% combined yield of the products 2A, 2B, and 2C.

2A: Cis-6-(4-Nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10b-octahydro-pyrrolo[2,1a]isoquinoline. 30.2 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.17 (d, J=8.8, 2H), 7.44 (d, J=8.6, 2H), 6.82 (d, J=2.5, 1H), 6.72 (dd, J=2.5, 8.7, 1H), 6.56 (d, J=8.7, 1H), 4.50 (m, 1H), 4.00 (t, J=5.7, 2H), 4.81 (br m, 1H), 3.56 (m, 1H), 3.48 (d, J=12.3, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 2.85 (m, 2H), 2.72 (m, 1H), 2.15 (m, 5H), 1.85 (d, J=14.6, 2H), 1.68 (m, 3H), 1.42 (m, 1H).

2B: Trans-6-(4-Nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10b-octahydro-pyrrolo[2,1a]isoquinoline. 21.4 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.23 (d, J=8.8, 2H), 7.43 (m, 3H), 7.02 (d, J=7.8, 1H), 6.95 (br d, J=7.8, 1H), 4.77 (br s, 1H), 3.97 (br s, 1H), 3.70 (br m, 3H), 3.29 (br m, 4H), 2.77 (m, 1H), 2.70 (m, 3H), 2.57 (br m, 1H), 2.22 (br s, 3H), 1.9 (br d, J=14.8, 2H), 1.75 (m, 1H), 1.73 (m, 5H), 1.49 (m, 1H).

2C: Trans-6-(4-Nitrophenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10b-octahydro-pyrrolo[2,1a]isoquinoline. 28.7 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.20 (d, J=8.8, 2H), 7.46 (t, J=8.0, 1H), 7.34 (br d, J=6.6, 2H), 7.04 (d, J=7.9, 1H), 7.00 (d, J=8.3, 1H), 4.88 (m, 1H), 3.86 (s, 6H), 4.08 (br s, 1H), 3.88 (br s, 2H), 3.76 (br s, 2H), 3.30 (m, 2H), 2.77 (m, 2H), 2.65 (m, 3H), 2.18 (m, 3H), 1.99 (br m, 1H), 1.82 4H), 1.70 (m, 2H), 1.47 (m, 1H).

Example 3

Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenylamine

A mixture of cis-6-(4-nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10b-octahydro-pyrrolo[2,1a]isoquinoline (Example 2, 310 mg, 0.71 mmol), PtO₂ (20 wt %, 62 mg), and ammonium formate (1.01 g, 16.0 mmol) in ethanol (13 mL) was purged with nitrogen and then heated to 75° C. overnight. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated. Purification by normal phase column chromatography (NH₃ in MeOH/CH₂Cl₂) followed by reverse-phase HPLC gave 19.6 mg (4%) of the desired product as the TFA salt. MS mass calcd for C₂₆H₃₅N₃O, 405.3; found 406.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.28 (m, 4H), 6.78 (d, J=2.5, 1H), 6.69 (m, 1H), 6.55 (d, J=8.7, 1H), 4.74 (m, 1H), 4.37 (m, 1H), 3.97 (t, J=5.8, 2H), 3.76 (m, 1H), 3.46 (m, 3H), 3.33 (m, 2H), 3.18 (m, 2H), 2.83 (m, 2H), 2.69 (m, 1H), 2.13 (m, 5H), 1.83 (d, J=14.6, 2H), 1.65 (m, 3H), 1.40 (m, 1H), 1.89 (t, J=7.3, 1H).

Example 4-(A-D)

4A: Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

4B: Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

4C: Cis-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

4D: Trans-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Nitrophenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale, to yield 1.31 g (83%) of the desired product as a mixture of diastereomers (yellow oil). MS: exact mass calcd for C₂₆H₃₅N₃O₄, 453.3; m/z found, 454.5 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 2.88 mmol scale to give a 34% combined yield of the products 4A, 4B, 4C, and 4D.

4A: Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 73.2 mg (4%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (acetone-d₆): 13.30 (br s, 1H), 11.68 (br s, 1H), 11.04 (br s, 1H), 8.23 (m, 1H), 8.16 (s, 1H), 7.80 (d, J=7.6, 1H), 7.73 (m, 1H), 6.98 (d, J=2.4, 1H), 6.79 (m, 1H), 6.67 (d, J=8.6, 1H), 4.93 (br s, 1H), 4.82 (m, 1H), 4.13 (t, J=5.9, 2H), 3.96 (br s, 1H), 3.77 (m, 1H), 3.65 (d, J=11.2, 3H), 3.45 (br s, 1H), 3.35 (br s, 2H), 3.01 (br s, 2H), 2.90 (m, 1H), 2.35 (m, 5H), 1.90 (br s, 4H), 1.75 (m, 1H), 1.5 (m, 1H).

4B: Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isopuinoline. 201.4 mg (10%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (acetone-d₆): 13.22 (br s, 1H), 11.5 (br s, 1H), 8.16 (m, 1H), 8.09 (s, 1H), 7.69 (m, 1H), 7.64 (m, 1H), 7.01 (br s, 1H), 6.87 (br m, 2H), 5.15 (br s, 1H), 4.83 (br s, 1H), 4.15 (m, 2H), 3.80 (br s, 3H), 3.64 (d, J=11.7, 2H), 3.57 (br s, 1H), 3.33 (s, 2H), 2.99 (s, 2H), 2.38 (br s, 1H), 2.32 (m, 2H), 2.20 (br m, 3H), 1.91 (m, 4H), 1.79 (m, 1H), 1.49 (m, 1H).

4C: Cis-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 38.3 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (acetone-d₆): 13.56 (br s, 1H), 11.42 (br s, 1H), 8.17 (d, J=7.4, 1H), 8.03 (s, 1H), 7.70 (br m, 2H), 7.40 (m, 1H), 7.06 (d, J=7.8, 1H), 6.95 (d, J=8.1, 1H), 4.94 (m, 2H), 4.01 (s, 1H), 3.83 (m, 1H), 3.74 (m, 1H), 3.48 (br s, 1H), 3.40 (m, 2H), 3.26 (m, 1H), 2.75 (m, 5H), 2.32 (m, 1H), 2.20 (m, 2H), 1.85 (m, 7H), 1.42 (br m, 1H).

4D: Trans-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 369.1 mg (18%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃N₃O₃, 435.3; m/z found, 436.5 [M+H]⁺. ¹H NMR (acetone-d₆): 13.29 (br s, 1H), 11.52 (br s, 1H), 8.16 (m, 1H), 8.10 (s, 1H), 7.67 (m, 2H), 7.02 (s, 1H), 6.88 (s, 2H), 6.23 (br s, 1H), 5.08 (s, 1H), 4.83 (br s, 1H), 4.17 (m, 2H), 3.78 (br s, 2H), 3.65 (d, J=11.2, 2H), 3.55 (br s, 1H), 3.35 (s, 2H), 2.99 (s, 2H), 2.70 (br s, 1H), 2.33 (m, 2H), 2.12 (m, 3H), 1.93 (m, 4H), 1.79 (m, 1H), 1.28 (m, 1H).

Example 5-(A-C)

5A: Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

5B: Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

5C: Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-p-tolyl-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale, to yield 1.3 g (87%) of the desired product as a mixture of diastereomers. MS: exact mass calcd for C₂₇H₃₈N₂O₂, 422.3; m/z found, 423.4 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 3.08 mmol scale, to give a 19% combined yield of the products 5A, 5B, and 5C.

5A: Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 22.0 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O, 404.3; m/z found, 405.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.09 (d, J=8.0, 2H), 7.04 (d, J=8.0, 2H), 6.82 (m, 1H), 6.66 (m, 1H), 6.53 (d, J=8.7, 1H), 4.79 (m, 1H), 4.40 (m, 1H), 4.00 (t, J=6.0, 2H), 3.82 (m, 1H), 3.50 (m, 3H), 3.30 (m, 1H), 3.25 (m, 1H), 3.18 (t, J=7.6, 2H), 2.79 (m, 3H), 2.22 (5, 3H), 2.17 (m, 4H), 2.09 (m, 1H), 1.76 (m, 4H), 1.67 (m, 1H), 1.39 (m, 1H).

5B: Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 200.1 mg (10%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O, 404.3; m/z found, 405.4 [M+H]⁺. ¹H NMR (acetone-d₆): 12.50 (br s, 1H), 11.21 (br s, 1H), 7.19 (d, J=8.0, 2H), 7.13 (d, J=7.9, 2H), 7.00 (br s, 1H), 6.84 (m, 2H), 5.18 (br s, 1H), 4.54 (s, 1H), 4.17 (m, 2H), 3.87 (m, 1H), 3.67 (m, 4H), 3.61 (br s, 1H), 3.37 (m, 2H), 3.03 (m, 2H), 2.76 (br s, 1H), 2.36 (m, 3H), 2.33 (m, 3H), 2.23 (m, 1H), 2.12 (m, 1H), 1.93 (m, 4H), 1.83 (m, 1H), 1.54 (m, 1H).

5C: Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 153.5 mg (8%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O, 404.3; m/z found, 405.5 [M+H]⁺. ¹H NMR (acetone-d₆): 11.61 (br s, 1H), 10.54 (br s, 1H), 7.42 (m, 1H), 7.14 (d, J=7.4, 2H), 7.07 (m, 1H), 7.02 (d, J=7.3, 2H), 6.98 (d, 8.2, 1H), 5.16 (br s, 1H), 4.79 (s, 1H), 4.17 (m, 1H), 3.97 (m, 1H), 3.89 (m, 2H), 3.80 (m, 1H), 3.50 (m, 1H), 3.34 (m, 2H), 2.89 (m, 1H), 2.69 (m, 1H), 2.60 (m, 3H), 2.30 (s, 2H), 2.27 (m, 3H), 2.18 (m, 1H), 2.06 (m, 1H), 1.77 (m, 5H), 1.75 (m, 1H), 1.45 (m, 1H).

Example 6-(A-B)

6A: Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

6B: Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

6C. Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-(3,4-Dichloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 1, Step 6, on a 2.53 mmol scale, to yield 0.96 g (80%) of the desired product as a mixture of diastereomers (yellow oil). MS: exact mass calcd for C₂₆H₃₄Cl₂N₂O₂, 476.2; m/z found, 477.3 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 2.01 mmol scale, to give a 25% combined yield of the desired products 6A and 6B.

6A: Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 20.0 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₂Cl₂N₂O, 458.2; m/z found, 459.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.61 (d, J=8.3, 1H), 7.51 (m, 1H), 7.32 (m, 1H), 6.95 (m, 1H), 6.79 (m, 1H), 6.68 (d, J=8.7, 1H), 4.90 (m, 1H), 4.66 (m, 1H), 4.12 (t, J=6.0, 2H), 3.93 (m, 1H), 3.70 (m, 1H), 3.61 (m, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 3.29 (t, J=7.6, 2H), 2.89 (m, 3H), 2.27 (m, 5H), 1.93 (m, 4H), 1.79 (m, 1H), 1.49 (m, 1H).

6B: Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 338.0 mg (24%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₂Cl₂N₂O, 458.2; m/z found, 459.3 [M+H]⁺. ¹H NMR (acetone-d₆): 11.35 (br s, 1H), 7.56 (d, J=10.1, 1H), 7.46 (m, 1H), 7.22 (m, 1H), 7.00 (br s, 1H), 6.89 (m, 2H), 5.13 (br s, 1H), 4.69 (br s, 1H), 4.18 (m, 2H), 3.76 (m, 2H), 3.67 (d, J=11.7, 2H), 3.56 (m, 1H), 3.35 (m, 2H), 3.03 (m, 2H), 2.79 (br s, 1H), 2.34 (m, 2H), 2.21 (m, 1H), 2.13 (m, 2H), 1.92 (m, 4H), 1.82 (m, 1H), 1.51 (m, 1H).

6C. Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 85 mg (6%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₂Cl₂N₂O, 458.2; m/z found, 459.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.41 (m, 3H), 7.06 (m, 2H), 6.98 (d, J=8.2, 1H), 5.09 (br s, 1H), 4.84 (br s, 1H), 4.15 (m, 1H), 3.92 (m, 3H), 3.76 (br s, 1H), 3.43 (m, 3H), 2.85 (m, 2H), 2.68 (m, 3H), 2.23 (m, 4H), 1.84 (m, 6H), 1.46 (m, 1H).

Example 7-(A-C)

7A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

7B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

7C: Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-2-(4-trifluoromethyl-phenyl)-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale, to yield 1.27 g (77%) of the desired product as a mixture of diastereomers (yellow oil). MS: exact mass calcd for C₂₇H₃₅F₃N₂O₂, 476.3; m/z found, 477.4 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 2.66 mmol scale, to give a 2% combined yield of the desired products 7A, 7B, and 7C.

7A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 6.4 mg (0.3%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃F₃N₂O, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.74 (d, J=7.9, 2H), 7.54 (d, J=7.9, 2H), 6.96 (br s, 1H), 6.78 (m, 1H), 6.61 (m, 1H), 4.89 (m, 1H), 4.73 (m, 1H), 4.11 (t, J=6.0, 2H), 3.71 (m, 1H), 3.69 (m, 1H), 3.60 (m, 2H), 3.49 (m, 1H), 3.36 (m, 1H), 3.28 (t, J=7.0, 2H), 2.91 (m, 3H), 2.27 (m, 5H), 1.87 (m, 4H), 1.77 (br s, 1H), 1.50 (m, 1H).

7B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 16.0 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃F₃N₂O, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.70 (d, J=8.1, 2H), 7.49 (d, J=8.0, 2H), 7.01 (br s, 1H), 6.90 (m, 1H), 6.79 (m, 1H), 5.14 (br s, 1H), 4.76 (br s, 1H), 4.16 (m, 2H), 3.75 (m, 2H), 3.65 (m, 2H), 3.55 (m, 1H), 3.34 (m, 2H), 2.99 (m, 2H), 2.78 (m, 1H), 2.33 (m, 2H), 2.22 (m, 1H), 2.13 (m, 1H), 1.94 (m, 6H), 1.81 (m, 1H), 1.52 (m, 1H).

7C: Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 16.0 mg (1%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃F₃N₂O, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.56 (d, J=11.3, 2H), 7.40 (t, J=8.0, 1H), 7.34 (d, J=7.9, 2H), 7.06 (d, J=7.8, 1H), 6.96 (d, J=8.2, 1H), 5.01 (br s, 1H), 4.87 (m, 1H), 4.11 (m, 1H), 3.87 (m, 1H), 3.76 (br s, 3H), 3.27 (m, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.62 (m, 3H), 2.20 (m, 3H), 2.00 (m, 1H), 1.80 (m, 6H), 1.43 (m, 1H).

Example 8-(A-F)

8A: Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

8B: 1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

8C: 1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

8D: Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

8E: Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

8F: Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Methoxy-Phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. To a solution of 1-[3-(3-pyrrolidin-2-yl-phenoxy)-propyl]-piperidine (6.93 mmol) and triethylamine (3.0 equiv.) in THF (0.1 M) under nitrogen was added 2-bromo-1-(4-methoxyphenyl)-ethanone (1.05-1.20 equiv.) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with CH₂Cl₂ and washed with 1.0 N NaOH followed by brine. The organic solution was dried (Na₂CO₃) and concentrated to give the crude product, which was purified by normal phase column chromatography (NH₃ in MeOH/CH₂Cl₂) to provide 2.21 g (73%) of the desired product as a yellow oil. MS: exact mass calcd for C₂₇H₃₆N₂O₃, 436.3; m/z found, 437.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.86 (dd, J=2.1, 6.9, 2H), 7.22 (m, 1H), 7.00 (d, J=1.6, 1H), 6.97 (m, 3H), 6.81 (m, 1H), 4.01 (m, 3H), 3.85 (s, 3H), 3.48 (t, J=8.0, 1H), 3.30 (m, 2H), 2.39 (m, 8H), 2.15 (m, 1H), 1.89 (m, 5H), 1.67 (m, 1H), 1.51 (m, 5H), 1.38 (br m, 1H). Alternatively, the reaction mixture may be concentrated and taken on to the next synthetic step without purification.

Step 2. 1-(4-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. To a 0° C. solution of the aminoalcohol obtained from Step 1 (2.29 mmol) in ethanol (0.1 M) was added NaBH₄ (1.5 equiv.), and the mixture was allowed to warm to rt. After completion of the reaction, the mixture was diluted with CH₂Cl₂ and washed with water and brine. The organic layer was dried (Na₂CO₃), filtered and concentrated to give the crude product. Normal phase chromatographic purification (NH₃ in MeOH/CH₂Cl₂) gave the desired product (820.7 mg, 83%) as a mixture of diastereomers. MS: exact mass calcd for C₂₇H₃₈N₂O₃, 438.3; m/z found, 439.4 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 1.72 mmol scale, to give a combined yield of 33% for the four diastereomers.

8A: Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 27.5 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.18 (d, J=8.6, 2H), 6.97 (d, J=8.8, 2H), 6.89 (d, J=2.4, 1H), 6.82 (dd, J=2.4, 8.7, 1H), 6.75 (d, J=8.7, 1H), 4.87 (m, 1H), 4.33 (m, 1H), 4.11 (t, J=5.8, 2H), 3.9 (m, 1H), 3.82 (s, 3H), 3.59 (m, 3H), 3.42 (m, 2H), 3.31 (m, 2H), 2.97 (m, 2H), 2.85 (m, 1H), 2.27 (m, 5H), 1.98 (d, J=14.6, 2H), 1.82 (m, 3H), 1.53 (m, 1H). The enantiomers were separated using a Chiralpak® AD column. The first eluting enantiomer was Example 8B: 1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. ([α]_(D) ²⁰=−66°, c=0.006, CH₂Cl₂). The second eluting compound was Example 8C: 1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. ([α]_(D) ²⁰=+68°, c=0.011, CH₂Cl₂).

8D: Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 101.5 mg (9%) as the TFA salt . MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.06 (br m, 2H), 6.91 (m, 5H), 4.95 (br s, 1H), 4.46 (br s, 1H), 4.14 (t, J=5.5, 2H), 3.79 (s, 3H), 3.76 (br s, 1H), 3.62 (m, 2H), 3.45 (br s, 1H), 3.33 (m, 2H), 2.98 (t, J=12.4, 2H), 3.74 (br s, 1H), 2.27 (m, 2H), 2.16 (br s, 2H), 1.97 (m, 2H), 1.85 (m, 3H), 1.54 (m, 1H).

8E: Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isopuinoline. 18.0 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.42 (m, 1H), 7.07 (br s, 2H), 6.98 (m, 4H), 4.56 (br s, 1H), 4.02 (br s, 1H), 3.78 (s, 3H), 3.70 (br m, 3H), 3.38 (m, 1H), 3.30 (m, 3H), 3.20 (m, 1H), 2.73 (br s, 1H), 2.63 (m, 3H), 2.35 (br m, 1H), 2.14 (br m, 3H), 1.80 (m, 4H), 1.69 (m, 3H), 1.49 (m, 1H).

8F: Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isopuinoline. 176.6 mg (20%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.37 (t, J=8.0, 1H), 6.96 (d, J=8.0, 3H), 6.92 (d, J=8.2, 1H), 6.87 (d, J=8.7, 2H), 4.78 (m, 1H), 4.66 (s, 1H), 4.08 (br m, 1H), 3.82 (m, 1H), 3.75 (m, 2H), 3.73 (s, 3H), 3.61 (br m, 1H), 3.27 (m, 3H), 2.75 (br m, 1H), 2.58 (m, 3H), 2.41 (m, 1H), 2.1-1.6 (m, 10H), 1.41 (m, 1H).

Example 9-(A-B)

9A: Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol

9B: Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol

Step 1. Acetic acid 4-(2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-acetyl)-phenyl ester. Prepared as described in Example 8, Step 1, on a 4.51 mmol scale. Chromatographic purification as described provided 450.1 mg (28%) of the desired product as yellow oil. MS: exact mass calcd for C₂₈H₃₆N₂O₄, 464.3; m/z found, 465.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.98 (m, 2H), 7.26 (m, 1H), 7.24 (m, 2H), 7.06 (d, J=1.5, 1H), 7.02 (d, J=7.5, 1H), 6.88 (m, 1H), 4.05 (m, 3H), 3.56 (m, 1H), 3.44 (d, J=15.5, 1H), 3.37 (m, 1H), 2.50 (m, 2H), 2.45 (m, 4H), 2.33 (s, 3H), 2.22 (m, 1H), 1.90 (m, 4H), 1.75 (m, 1H), 1.58 (m, 4H), 1.46 (br m, 2H).

Step 2. 4-(1-Hydroxy-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethyl)-phenol. Prepared as described in Example 8, Step 2, on a 0.896 mmol scale, to give crude material that was taken on to the next step without purification. MS: exact mass calcd for C₂₆H₃₆N₂O₃, 424.3; m/z found, 425.5 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 0.896 mmol scale, to give a combined yield of 16% of two diastereomers.

9A: Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol. 27.2 mg (5%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O₂, 406.3; m/z found, 407.5 [M+H]⁺. ¹H NMR (acetone-d₆): 12.51 (br s, 1H), 11.35 (br s, 1H), 7.63 (br s, 3H), 7.04 (d, J=8.4, 2H), 6.95 (s, 1H), 6.82 (m, 4H), 5.14 (br s, 1H), 4.44 (br s, 1H), 4.13 (br m, 2H), 3.84 (br s, 1H), 3.64 (m, 5H), 3.34 (br s, 2H), 2.99 (br m, 2H), 2.72 (br s, 1H), 2.30 (m, 2H), 2.17 (br m, 1H), 2.09 (br m, 1H), 1.91 (m, 4H), 1.80 (m, 1H), 1.48 (m, 1H).

9B: Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol. 68.8 mg (11%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O₂, 406.3; m/z found, 407.5 [M+H]⁺. ¹H NMR (acetone-d₆): 10.96 (br s, 1H), 10.36 (br s, 3H), 9.59 (br s, 1H), 7.39 (m, 1H), 7.03 (d, J=7.5, 1H), 6.94 (m, 4H), 6.77 (d, J=7.8, 2H), 5.13 (br s, 1H), 4.69 (br s, 1H), 4.14 (br m, 1H), 3.84 (m, 4H), 3.49 (br s, 1H), 3.39 (m, 2H), 2.87 (d, J=8.4, 1 H), 2.64 (br m, 3H), 2.53 (br m, 1H), 2.24 (m, 3H), 2.05 (br s, 1H), 1.80 (m, 5H), 1.46 (br m, 1H).

Example 10-(A-C)

10A: Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

10B: Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-l-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

10C: Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 4.33 mmol scale. Chromatographic purification provided 1.37 g (72%) of the desired product as an orange oil. MS: exact mass calcd for C₂₇H₃₆N₂O₃, 436.3; m/z found, 437.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.44 (m, 2H), 7.28 (m, 1H), 7.21 (m, 1H), 7.07 (d, J=2.6, 1H), 6.97 (m, 2H), 6.79 (m, 1H), 4.07 (d, J=16.3, 1H), 3.98 (m, 2H), 3.83 (s, 3H), 3.45 (m, 3H), 2.54 (m, 3H), 2.47 (m, 3H), 2.37 (m, 1H), 2.19 (m, 1H), 2.00 (m, 3H), 1.82 (m, 2H), 1.63 (m, 4H), 1.45 (m, 2H).

Step 2. 1-(3-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 8, Step 2, on a 1.8 mmol scale, to give 420 mg (53%) of the desired product as a mixture of diastereomers which were not separated. MS: exact mass calcd for C₂₇H₃₈N₂O₃, 438.3; m/z found, 439.5 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 0.91 mmol scale, to give a 48% combined yield of the desired products.

10A: Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 57.3 mg (10%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.32 (t, J=8.1, 1H), 6.93 (m, 2H), 6.91 (m, 2H), 6.78 (dd, J=2.6, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.91 (m, 1H), 4.54 (dd, J=4.6, 12.1, 1H), 4.12 (t, J=6.0, 2H), 3.88 (m, 1H), 3.78 (5, 3H), 3.64 (m, 3H), 3.47 (m, 1H), 3.38 (m, 1H), 3.30 (m, 2H), 2.93 (m, 3H), 2.31 (m, 4H), 2.86 (m, 1H), 1.84 (m, 4H), 1.78 (m, 1H), 1.50 (m, 1H).

10B: Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 122.0 mg (21%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.30 (t, J=7.9, 1H), 6.98 (br s, 1H), 6.91 (m, 1H), 6.83 (m, 4H), 5.15 (br s, 1H), 4.57 (br s, 1H), 4.16 (m, 2H), 3.86 (br s, 1H), 3.77 (s, 3H), 3.66 (m, 4H), 3.36 (m, 2H), 3.01 (br s, 2H), 2.75 (m, 1H), 2.34 (m, 2H), 2.22 (m, 1H), 2.15 (m, 1H), 1.91 (m, 4H), 1.80 (m, 1H), 1.55 (m, 1H).

10C: Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 85.0 mg (14%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.41 (t, J=8.0, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 6.97 (d, J=8.2, 1H), 6.84 (m, 1H), 6.76 (5, 1H), 6.67 (m, 1H), 5.16 (br s, 1H), 4.79 (br s, 1H), 4.16 (br s, 1H), 3.90 (m, 4H), 3.77 (s, 3H), 3.37 (m, 3H), 2.86 (m, 1H), 2.65 (m, 4H), 2.23 (m, 3H), 2.10 (m, 1H), 2.05 (br s, 1H), 1.77 (m, 5H), 1.49 (m, 1H).

Example 11-(A-C)

11A: Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

11B: Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

11C: Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 5.63 mmol scale. Chromatographic purification gave 1.35 g (71%) of the desired product as an orange oil. MS: exact mass calcd for C₂₆H₃₃ClN₂O₂, 440.2; m/z found, 441.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.85 (m, 1H), 7.73 (m, 1H), 7.48 (m, 1H), 7.33 (t, J=3.9, 1H), 7.23 (t, J=7.8, 1H), 6.95 (m, 2H), 6.78 (dd, J=1.9, 8.2, 1H), 4.01 (d, J=15.9, 1H), 3.98 (t, J=6.3, 2 H), 3.43 (m, 1H), 3.36 (m, 2H), 2.58 (m, 2H), 2.51 (m, 4H), 2.35 (m, 1H), 2.20 (m, 1H), 2.01 (m, 4H), 1.81 (m, 2H), 1.66 (m, 4H), 1.47 (m, 2H).

Step 2. 1-(3-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 8, Step 2, on a 1.83 mmol scale, to give 610 mg (75%) of the desired product as a mixture of diastereomers, which were not separated. MS: exact mass calcd for C₂₆H₃₅ClN₂O₂, 442.2; m/z found, 443.5 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 1.35 mmol scale, to give a 16% combined yield of the desired products.

11A: Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 37.0 mg (4%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.45 (m, 2H), 7.33 (m, 2H), 6.97 (m, 1H), 6.81 (dd, J=2.6, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.95 (m, 2H), 4.63 (m, 1H), 4.14 (m, 2H), 3.98 (m, 1H), 3.72 (m, 3H), 3.55 (m, 1H), 3.46 (m, 1H), 3.36 (m, 2H), 3.01 (m, 2H), 2.91 (m, 1H), 2.36 (m, 5H), 1.94 (s, 3H), 1.80 (m, 1H), 1.52 (m, 1H).

11B: Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 38 mg (4%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.36 (m, 3H), 7.24 (m, 1H), 6.99 (br 5, 1H), 6.85 (m, 1H), 6.81 (m, 1H), 5.14 (br s, 2H), 4.65 (br s, 1H), 4.17 (m, 2H), 3.68 (m, 6H), 3.33 (m, 2H), 2.98 (m, 2H), 2.76 (m, 1H), 2.32 (m, 2H), 2.22 (m, 2H), 1.91 (m, 4H), 1.80 (m, 1H), 1.53 (m, 1H).

11C: Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 69 mg (8%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.43 (t, J=8.0, 1H), 7.30 (br s, 2H), 7.26 (5, 1H), 7.07 (m, 2H), 6.99 (d, J=8.2, 1H), 5.15 (br 5, 1H), 4.85 (br 5, 1H), 4.15 (m, 1H), 3.89 (m, 3H), 3.78 (m, 1H), 3.44 (m, 3H), 2.86 (m, 1H), 2.78 (m, 1H), 2.62 (m, 3H), 2.23 (m, 3H), 2.10 (m, 2H), 1.85 (m, 5H), 1.49 (m, 1H).

Example 12-(A-D)

12A: Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

12B: Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

12C: Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

12D: Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(2-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 5.63 mmol scale. Chromatographic purification gave 1.37 g (72%) of the desired product as an orange oil. MS: exact mass calcd for C₂₆H₃₃ClN₂O₂, 440.2; m/z found, 441.5 [M+H]⁺.

Step 2. 1-(2-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 8, Step 2, on a 1.83 mmol scale, to give 375 mg (46%) of the desired product as a mixture of diastereomers, which were not separated. MS: exact mass calcd for C₂₆H₃₅ClN₂O₂, 442.2; m/z found, 443.5 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 1.35 mmol scale, to give a 24% combined yield of the desired products.

12A: Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 13.3 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.54 (m, 1H), 7.37 (m, 2H), 7.20 (br s, 1H), 7.02 (s, 1H), 6.80 (m, 1H), 6.61 (d, J=8.8, 1H), 5.13 (br s, 1H), 4.86 (br s, 1H), 4.13 (s, 2H), 3.88 (br s, 1H), 3.74 (m, 3H), 3.44 (m, 2H), 3.30 (m, 2H), 2.89 (m, 4H), 2.30 (m, 5H), 1.92 (m, 4H), 1.58 (m, 1H).

12B: Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 53 mg (8%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.51 (m, 1H), 7.35 (m, 1H), 7.29 (m, 1H), 7.08 (m, 2H), 6.87 (m, 2H), 5.15 (m, 1H), 4.99 (m, 1H), 4.71 (m, 2H), 4.19 (m, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.35 (m, 2H), 3.00 (m, 2H), 2.82 (br s, 1H), 2.34 (m, 2H), 2.19 (m, 3H), 1.92 (m, 4H), 1.81 (m, 1H), 1.54 (m, 1H).

12C: Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 49.2 mg (7%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.45 (d, J=7.9, 1H), 7.20 (m, 2H), 7.07 (m, 1H), 6.87 (d, J=7.7, 1H), 6.76 (m, 2H), 4.91 (br s, 1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.40 (m, 2H), 3.24 (1H), 3.11 (m, 2H), 3.79 (m, 4H), 2.62 (m, 3H), 2.46 (m, 2H), 2.02 (m, 2H), 1.77 (m, 4H), 1.61 (m, 2H), 1.40 (m, 1H).

12D: Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 50 mg (7%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.57 (d, J=11.4, 1H), 7.43 (m, 1H), 7.31 (m, 1H), 7.08 (m, 2H), 6.97 (d, J=8.2, 1H), 6.73 (br s, 1H), 5.19 (br s, 1H), 5.07 (br s, 1H), 4.29 (m, 1H), 3.86 (m, 4H), 3.53 (m, 2H), 3.38 (m, 1H), 2.89 (m, 1H), 2.69 (m, 4H), 2.30 (m, 3H), 2.10 (m, 1H), 1.90 (m, 1H), 1.87 (m, 5H), 1.51 (m, 1H).

Example 13-(A-B)

13A: Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

13B: Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(2-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale. Chromatographic purification gave 1.12 g (74%) of the desired product as an orange semi-solid. MS: exact mass calcd for C₂₇H₃₆N₂O₃, 436.3; m/z found, 437.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.63 (dd, J=1.8, 7.7, 1H), 7.40 (m, 1H), 7.18 (m, 1H), 6.94 (m, 3H), 6.87 (d, J=8.3, 1H), 6.75 (m, 1H), 4.10 (d, J=18.0, 1H), 3.96 (t, J=6.4, 2H), 3.72 (s, 3H), 3.52 (m, 3H), 2.50 (m, 2H), 2.45 (m, 4H), 2.16 (m, 1H), 1.97 (m, 3H), 1.84 (m, 2H), 1.75 (m, 1H), 1.60 (m, 4H), 1.44 (m, 2H).

Step 2. 1-(2-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 8, Step 2, on a 2.18 mmol scale, to give 930 mg (97%) of the desired product as a mixture of diastereomers, which were not separated. MS: exact mass calcd for C₂₇H₃₈N₂O₃, 438.3; m/z found, 439.6 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 2.05 mmol scale, to give a 20% combined yield of two diastereomers.

13A: Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 27.3 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.35 (m, 1H), 7.14 (br s, 1H), 7.09 (d, J=8.2, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 6.75 (m, 1H), 6.63 (d, J=8.6, 1H), 4.92 (m, 2H), 4.11 (t, J=6.0, 2H), 3.95 (m, 1H), 3.76 (m, 3H), 3.62 (m, 4H), 3.37 (m, 1H), 3.30 (m, 2H), 2.97 (m, 2H), 2.88 (m, 1H), 2.30 (m, 5H), 2.0 (m, 4H), 1.79 (m, 1H), 1.51 (m, 1H).

13B: Trans- 6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 235 mg (18%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (acetone-d₆): 11.54 (br s, 1H), 10.48 (m, 2H), 7.42 (m, 1H), 7.27 (m, 1H), 7.11 (d, J=8.1, 1H), 7.06 (m, 1H), 6.98 (d, J=11.8, 1H), 6.74 (m, 1H), 6.51 (m, 1H), 5.11 (br s, 1H), 4.96 (br s, 1H), 4.13 (m, 1H), 3.98 (s, 3H), 3.89 (m, 2H), 3.70 (m, 1H), 3.43 (m, 2H), 3.33 (m, 1H), 2.87 (m, 1H), 2.62 (m, 3H), 2.25 (m, 3H), 2.03 (m, 1H), 1.82 (m, 5H), 1.48 (m, 1H).

Example 14-(A-C)

14A: Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

14B: Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

14C: Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Fluoro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale. Chromatographic purification gave 1.24 g (84%) of the desired product. MS: exact mass calcd for C₂₆H₃₃FN₂O₂, 424.3; m/z found, 425.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.90 (m, 2H), 7.22 (m, 1H), 7.06 (m, 2H), 7.95 (m, 2H), 6.79 (m, 1H), 4.03 (d, J=15.7, 1H), 3.98 (m, 2H), 3.39 (m, 3H), 2.52 (t, J=7.4, 2H), 2.45 (br s, 3H), 2.36 (m, 1H), 2.18 (m, 2H), 2.00 (m, 3H), 1.80 (m, 2H), 1.62 (m, 4H), 1.45 (m, 2H).

Step 2. 1-(4-Fluoro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 8, Step 2, on a 2.47 mmol scale, to give 980 mg (93%) of the desired product as a mixture of diastereomers and regioisomers, which were not separated. MS: exact mass calcd for C₂₆H₃₅FN₂O₂, 426.3; m/z found, 427.5 [M+H]⁺.

Step 3. Performed as described in Example 1, Step 7, on a 2.23 mmol scale to give a 12% combined yield of the desired products.

14A: Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 28.0 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃FN₂O, 408.3; m/z found, 409.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.33 (m, 2H), 7.17 (t, J=8.8, 2H), 6.95 (d, J=2.6, 1H), 6.78 (dd, J=2.6, 8.7, 1H), 6.64 (d, J=8.7, 1H), 4.91 (m, 1H), 4.61 (m, 1H), 4.26 (m, 4H), 4.12 (t, J=6.0, 2H), 3.94 (m, 1H), 3.62 (m, 3H), 3.45 (m, 2H), 3.31 (m, 2H), 2.92 (m, 3H), 2.32 (m, 5H), 1.78 (m, 1H), 1.50 (m, 1H).

14B: Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 9.7 mg (0.6%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃FN₂O, 408.3; m/z found, 409.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.30 (m, 2H), 7.13 (t, J=8.7, 2H), 7.00 (br s, 1H), 6.85 (m, 2H), 5.15 (br s, 1H), 4.63 (br s, 1H), 4.17 (m, 2H), 3.85 (m, 1H), 3.66 (m, 4H), 3.59 (m, 1H), 3.33 (m, 2H), 3.01 (m, 2H), 2.78 (m, 1H), 2.34 (m, 2H), 2.22 (m, 2H), 2.14 (m, 1H), 1.92 (m, 4H), 1.82 (m, 1H), 1.53 (m, 1H).

14C: Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 124.8 mg (9%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃FN₂O, 408.3; m/z found, 409.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.42 (m, 1H), 7.17 (m, 2H), 7.06 (m, 3H), 6.98 (d, J=8.2, 1H), 5.12 (br s, 1H), 4.83 (s, 1H), 4.15 (br s, 1H), 3.89 (m, 3H), 3.77 (m, 1H), 3.43 (m, 3H), 3.78 (m, 5H), 2.24 (m, 4H), 1.85 (m, 6H), 1.49 (m, 1H).

Example 15

Cis-3-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol

To a solution of cis-6-(3-methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (27.0 mg, 0.042 mmol) in CH₂Cl₂ (0.2 mL) was added BBr₃ (1 M in CH₂Cl₂, 0.21 mL) and the reaction mixture was stirred at rt for 15 min. The reaction was quenched with water and the mixture was concentrated under a stream of N₂. The crude material was purified by reverse-phase HPLC to give 14.1 mg (53%) of the desired product as a TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O₂, 406.3; m/z found, 407.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.20 (m, 1H), 6.92 (m, 1H), 6.78 (m, 5H), 4.83 (m, 1H), 4.46 (m, 1H), 4.11 (t, J=7.2, 2H), 3.87 (m, 1H), 3.59 (m, 2H), 3.38 (m, 2H), 3.28 (m, 2H), 2.89 (m, 3H), 2.87 (m, 2H), 2.29 (m, 5H), 1.88 (m, 4H), 1.57 (m, 2H).

Example 16

Cis-2-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenol

Prepared as described in Example 15, on a 0.030 mmol scale, to give 3.6 mg (19%) of the desired product after chromatography. MS: exact mass calcd for C₂₆H₃₄N₂O₂, 406.3; m/z found, 407.4 [M+H]⁺. ¹H NMR (acetone-d₆): 6.87 (m, 7H), 4.92 (br s, 1H), 4.10 (t, J=5.9, 2H), 3.61 (m, 3H), 3.41 (m, 1H), 3.30 (m, 2H), 2.95 (m, 5H), 2.29 (m, 4H), 2.07 (m, 2H), 1.89 (m, 6H), 1.52 (m, 1H).

Example 17

Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.35 g (79%) of the desired product as a viscous oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₇H₃₃F₃N₂O₃, 474.2; m/z found, 475.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.77 (d, J=8.7, 2H), 7.11 (d, J=8.5, 2H), 7.05 (t, J=7.9, 1H), 6.82 (d, J=1.4, 1H), 6.78 (d, J=7.5, 1H), 6.64 (dd, J=2.3, 8.1, 1H), 3.80 (m, 3H), 3.3 (m, 2H), 2.31 (m, 5H), 2.21 (m, 1H), 1.96 (m, 1H), 1.81 (m, 3H), 1.60 (m, 2H), 1.45 (m, 4H), 1.31 (m, 2H).

Step 2. 9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 1, Step 7, on a 1.03 mmol scale, to give 445 mg (85%) of crude product, which was carried forward without purification. MS: exact mass calcd for C₂₇H₃₀F₃N₂O₂ ⁺, 471.2; m/z found, 471.5 [M]⁺.

Step 3. A mixture of isoquinolinium salt (Step 2, 0.878 mmol), bromocresol green (1-5 mg), and NaCNBH₃ (approx. 10 equiv.) in methanol (0.1 M) was stirred for 10 min at rt. The mixture was treated with methanolic HCl until the pH=4-5 (indicator turned yellow). More methanolic HCl was added when the solution takes on a green cast. When the reaction was complete, the mixture was diluted with CH₂Cl₂, and washed with 2 N NaOH, water (×2), and brine. The organic extract was dried (Na₂CO₃), filtered, and concentrated to provide the crude product. Purification by normal phase column chromatography (NH₃ in MeOH/CH₂Cl₂) followed by reverse-phase HPLC gave the desired compound (311.6 mg, 48%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃F₃N₂O₂, 474.3; m/z found, 475.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.53 (d, J=8.6, 2H), 7.46 (d, J=8.1, 2H), 7.05 (d, J=2.4, 1H), 6.97 (dd, J=2.3, 8.7, 1H), 6.84 (d, J=8.7, 1H), 5.03 (m, 1H), 4.65 (m, 1H), 4.25 (t, J=5.7, 2H), 4.01 (m, 1H), 3.74 (m, 3H), 3.57 (m, 2H), 3.45 (m, 2H), 3.11 (m, 2H), 2.95 (m, 1H), 2.41 (m, 5H), 2.10 (m, 2H), 1.99 (m, 3H), 1.69 (m, 1H).

Example 18

Cis-6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-Bromo-1-(3,4-dimethoxy-phenyl)-ethanone. To a 0° C. solution of 3,4-dimethoxyacetophenone (5.00 g, 27.8 mmol) in diethyl ether (200 mL) and CHCl₃ (30 mL) was added, dropwise over 1.5 h, a solution of Br₂ (1.45 mL, 27.8 mmol) in CHCl₃ (30 mL). Once the addition was complete, the mixture was stirred for 1 h at 0° C., and then was allowed to warm to rt. The reaction mixture was concentrated and the residue chromatographed (CH₂Cl₂/hexanes) to give 5.23 g (73%) of the ketone as a pale yellow solid. ¹H NMR (DMSO-d₆): 7.68 (dd, J=2.0, 8.4, 1H), 7.47 (d, J=2.0, 1H), 7.08 (d, J=8.5, 1H), 4.85 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H).

Step 2. 1-(3,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.30 g (77%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₈H₃₈N₂O₄, 466.3; m/z found, 467.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.40 (m, 1H), 7.35 (d, J=2.0, 1H), 7.17 (m, 1H), 6.96 (m, 1H), 6.91 (d, J=7.6, 1H), 6.81 (d, J=8.5, 1H), 6.76 (m, 1H), 3.91 (m, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.40 (m, 3H), 2.40 (m, 6H), 2.28 (m, 1H), 2.11 (m, 1H), 1.91 (m, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 1.54 (m, 4H), 1.41 (m, 2H).

Step 3. 6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.42 mmol scale, to give 1.05 g (89%) of crude product. MS: exact mass calcd for C₂₈H₃₅N₂O₃ ⁺, 447.3; m/z found, 447.5 [M]⁺.

Step 4. Prepared as described in Example 17, Step 3, on a 2.16 mmol scale, to give 420.2 mg (27%) of the desired product as the TFA salt after normal phase chromatography and HPLC. MS: exact mass calcd for C₂₈H₃₈N₂O₃, 450.3; m/z found, 451.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.12 (d, J=8.4, 1H), 7.03 (d, J=2.3, 1H), 6.95 (m, 3H), 6.90 (d, J=8.7, 1H), 5.02 (m, 1H), 4.51 (m, 1H), 4.25 (t, J=5.7, 2H), 4.01 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.74 (d, J=11.9, 3H), 3.45 (m, 2H), 3.10 (m, 2H), 2.92 (m, 1H), 2.43 (m, 5H), 2.10 (d, J=14.9, 2H), 1.97 (m, 3H), 1.68 (m, 1H).

Example 19

Cis-6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(2,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.28 g (78%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₈H₃₈N₂O₄, 466.3; m/z found, 467.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.16 (m, 1H), 7.10 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6, 1H), 6.87 (m, 2H), 6.76 (m, 1H), 4.04 (m, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.39 (m, 6H), 2.30 (m, 1H), 2.11 (m, 1H), 1.92 (m, 3H), 1.82 (m, 1H), 1.75 (m, 1H), 1.55 (m, 4H), 1.42 (m, 2H).

Step 2. 6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.90 mmol scale, to give 1.15 g (82%) of crude product. MS: exact mass calcd for C₂₈H₃₅N₂O₃ ⁺, 447.3; m/z found, 447.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.39 mmol scale, to give 91.9 mg (8%) of the desired product as the TFA salt after chromatography and HPLC. MS: exact mass calcd for C₂₈H₃₈N₂O₃, 450.3; m/z found, 451.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 6.76 (d, J=8.0, 1H), 6.67 (m, 2H), 6.59 (dd, J=2.5, 8.5, 1H), 6.52 (d, J=2.5, 1H), 6.37 (dd, J=2.5, 8.3, 1H), 4.53 (br s, 1H), 3.94 (t, J=6.0, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 2.89 (m, 2H), 2.79 (m, 1H), 2.71 (dd, J=5.5, 11.0, 1H), 2.50 (t, J=7.5, 2H), 2.44 (br s, 3H), 2.31 (m, 1H), 1.93 (m, 3H), 1.85 (m, 2H), 1.60 (m, 4H), 1.46 (br s, 2H).

Example 20

Cis-6-(2,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(2,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.27 g (78%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₈H₃₈N₂O₄, 466.3; m/z found, 467.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.14 (m, 1H), 7.09 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6, 1H), 6.88 (m, 1H), 6.75 (m, 1H), 4.03 (d, J=18.4, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.40 (m, 6H), 2.30 (m, 1H), 2.15 (m, 1H), 1.90 (m, 3H), 1.80 (m, 1H), 1.75 (m, 1H), 1.55 (m, 4H), 1.41 (m, 2H).

Step 2. 6-(2,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.38 mmol scale, to give 1.01 g (88%) of crude product. MS: exact mass calcd for C₂₈H₃₅N₂O₃ ⁺, 447.3; m/z found, 447.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.10 mmol scale, to give 354.4 mg (38%) of the desired product after recrystallization from methanol. MS: exact mass calcd for C₂₈H₃₈N₂O₃, 450.3; m/z found, 451.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 6.87 (d, J=8.9, 1H), 6.78 (d, J=8.4, 1H), 6.67 (m, 3H), 6.55 (d, J=3.1, 1H), 4.55 (d, 2.9, 1H), 3.99 (m, 2H), 3.84 (s, 3H), 3.57 (s, 3H), 3.15 (m, 1H), 3.03 (m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.3 (m, 8H), 1.51 (m, 4H), 1.40 (m, 2H).

Example 21

Cis-6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-Bromo-1-(3,5-dimethoxy-phenyl)-ethanone. Prepared as described in Example 18, Step 1, on a 11.1 mmol scale, to give 2.70 g (85%) of the ketone as a white solid. MS: exact mass calcd for C₁₀H₁₁BrO₃, 258.0; m/z found, 281.2 [M+Na]⁺. ¹H NMR (acetone-d₆): 7.15 (d, J=2.3, 2H), 6.75 (d, J=2.2, 1H), 4.75 (s, 2H), 3.85 (s, 6H).

Step 2. 1-(3,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.80 mmol scale, to give 1.10 g (90%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₈H₃₈N₂O₄, 466.3; m/z found, 467.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.16 (t, J=7.8, 1H), 6.95 (m, 3H), 6.90 (d, J=7.5, 1H), 6.75 (m, 1H), 6.33 (m, 1H), 3.93 (m, 3H), 3.76 (s, 6H), 3.43 (m, 2H), 3.37 (m, 1H), 2.48 (m, 6H), 2.33 (m, 1H), 2.15 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.69 (m, 1H), 1.60 (m, 4H), 1.46 (br s, 2H).

Step 3. 6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.03 mmol scale to give 700 mg (71%) of crude product. The crude product was taken on to the next step without characterization.

Step 4. Prepared as described in Example 17, Step 3, on a 1.45 mmol scale, to give 52.2 mg (5%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₈H₃₈N₂O₃, 450.3; m/z found, 451.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 6.89 (d, J=2.2, 1H), 6.83 (m, 2H), 6.49 (m, 1H), 6.42 (s, 2H), 4.87 (m, 1H), 4.37 (m, 1H), 4.11 (t, J=5.7, 2H), 3.87 (m, 1H), 3.77 (s, 6H), 3.61 (m, 3H), 3.44 (m, 2H), 3.31 (m, 2H), 2.94 (m, 2H), 2.81 (m, 1H), 2.27 (m, 5H), 1.97 (m, 2H), 1.85 (m, 3H), 1.60 (m, 1H).

Example 22

Cis-6-(3,4,5-Trimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-Bromo-1-(3,4,5-trimethoxy-phenyl)-ethanone. Prepared as described in Example 18, Step 1, on a 9.51 mmol scale, to give 2.23 g (80%) of the ketone as a white solid. MS (electron impact): exact mass calcd for C₁₁H₁₃BrO₄, 288.0; m/z found, 288 [M]⁺. ¹H NMR (acetone-d₆): 7.35 (s, 2H), 4.76 (s, 2H), 3.90 (s, 6H), 3.81 (s, 3H).

Step 2. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3,4,5-trimethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.47 g (85%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₉H₄₀N₂O₅, 496.3; m/z found, 497.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.10 (m, 3H), 6.86 (m, 2H), 6.68 (m, 1H), 3.85 (m, 3H), 3.72 (s, 6H), 3.71 (s, 3H), 3.35 (m, 2H), 3.22 (m, 1H), 2.36 (m, 6H), 2.07 (m, 1H), 1.86 (m, 3H), 1.72 (m, 1H), 1.65 (m, 1H), 1.50 (m, 4H), 1.37 (br s, 2H).

Step 3. 9-(3-Piperidin-1-yl-propoxy)-6-(3,4,5-trimethoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.76 mmol scale to give 1.17 g (83%) of crude product. MS: exact mass calcd for C₂₉H₃₇N₂O₄ ⁺, 477.3; m/z found, 477.5 [M]⁺.

Step 4. Prepared as described in Example 17, Step 3, on a 2.28 mmol scale, to give 175.0 mg (10%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₉H₄₀N₂O₄, 480.3; m/z found, 481.6 [M+H]⁺. ¹H NMR (MeOH-d₄): 6.78 (d, J=2.3, 1H), 6.73 (m, 2H), 6.46 (s, 2H), 4.24 (m, 1H), 4.00 (t, J=5.7, 2H), 3.77 (m, 1H), 3.70 (s, 6H), 3.67 (s, 3H), 3.49 (m, 3H), 3.35 (m, 2H), 3.20 (m, 2H), 2.85 (m, 2H), 2.72 (m, 1H), 2.20 (m, 5H), 1.86 (d, J=14.6, 2H), 1.72 (m, 3H), 1.42 (m, 1H).

Example 23

Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiophen-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.24 g (85%) of the desired product as an oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₄H₃₂N₂O₂S, 412.2; m/z found, 413.6 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.75 (m, 2H) 7.18 (t, J=8.0, 1H), 7.09 (dd, J=4.0, 5.0, 1H), 7.0 (m, 1H), 6.94 (d, J=7.6, 1H), 6.77 (m, 1H), 4.88 (s, 1H), 3.96 (m, 2H), 3.88 (d, J=16.4, 1H), 3.47 (d, J=8.8, 1H), 3.42 (d, J=16.0, 1H), 3.37 (m, 1H), 3.34 (s, 2H), 2.43 (m, 7H), 2.18 (m, 1H), 1.94 (m, 3H), 1.86 (m, 1H), 1.76 (m, 1H), 1.59 (m, 4H), 1.45 (br m, 2H).

Step 2. 9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-y1-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.90 mmol scale, to give 1.14 g (92%) of crude product. MS: exact mass calcd for C₂₄H₂₉N₂OS⁺, 393.2; m/z found, 393.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.90 mmol scale, to give 725.8 mg (41%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₄H₃₂N₂OS, 396.2; m/z found, 397.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.43 (m, 1H), 7.12 (s, 1H), 7.08 (m, 1H), 6.90 (m, 3H), 4.84 (m, 1H), 4.83 (m, 1H), 4.12 (t, J=5.7, 2H), 3.92 (br m, 1H), 3.71 (m, 1H), 3.60 (d, J=11.5, 2H), 3.46 (m, 2H), 3.31 (m, 2H), 2.97 (m, 2H), 2.85 (m, 1H), 2.25 (m, 5H), 1.95 (d, J=14.8, 2H), 1.84 (m, 3H), 1.53 (m, 1H).

Example 24-(A-B)

24A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-y1-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

24B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-y1-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-Bromo-1-thiophen-3-yl-ethanone. Prepared as described in Example 18, Step 1, on a 39.6 mmol scale, to give 6.89 g (85%) of the ketone as a white solid. ¹H NMR (acetone-d₆): 8.46 (m, 1H), 7.56 (m, 2H), 4.63 (s, 2H).

Step 2. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiophen-3-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.19 g (82%) of the desired product as an oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₄H₃₂N₂O₂S, 412.2; m/z found, 413.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.18 (m, 1H), 7.40 (m, 2H), 7.19 (m, 1H), 7.01 (s, 1H), 6.95 (d, J=7.6, 1H), 6.80 (m, 1H), 4.87 (s, 1H), 4.02 (m, 2H), 3.44 (m, 3H), 3.00 (m, 8H), 2.34 (m, 1H), 2.13 (m, 4H), 1.91 (m, 1H), 1.83 (m, 1H), 1.76 (m, 6H), 1.57 (m, 3H).

Step 3. 9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-y1-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.46 mmol scale, to give 779.2 mg (74%) of crude product. The crude product was taken on to the next step without characterization.

Step 4. Performed as described in Example 17, Step 3, on a 1.82 mmol scale, to give the diastereomers in a combined yield of 56%.

24A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 587.7 mg (51%) as the TFA salt. MS: exact mass calcd for C₂₄H₃₂N₂OS, 396.2; m/z found, 397.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.44 (m, 1H), 7.36 (5, 1H), 6.92 (d, J=4.4, 1H), 6.86 (d, J=2.2, 1H), 6.76 (m, 2H), 4.84 (m, 1H), 4.58 (m, 1H), 4.06 (t, J=5.8, 2H), 3.85 (m, 1H), 3.55 (m, 3H), 3.35 (m, 2H), 3.26 (m, 2H), 2.93 (m, 2H), 2.78 (m, 1H), 2.23 (m, 5H), 1.91 (m, 2H), 1.82 (m, 3H), 1.51 (m, 1H).

24B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 51.2 mg (4%) as the TFA salt. MS: exact mass calcd for C₂₄H₃₂N₂OS, 396.2; m/z found, 397.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.38 (br s, 1H), 6.96 (br s, 1H), 6.94 (br d, J=1.5, 1H), 6.83 (m, 3H), 4.78 (m, 1H), 4.48 (br s, 1H), 4.04 (t, J=5.7, 2H), 3.69 (br m, 2H), 3.51 (d, J=12.0, 3H), 3.33 (br s, 1H), 3.21 (m, 2H), 2.88 (m, 2H), 2.67 (br s, 1H), 2.15 (m, 2H), 2.07 (br m, 3H), 1.87 (d, J=14.5, 2H), 1.73 (m, 3H), 1.46 (m, 1H).

Example 25

Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyridin-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 749.2 mg (52%) of crude product after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₅H₃₃N₃O₂, 407.3; m/z found, 408.5 [M+H]⁺.

Step 2. 9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 1.36 mmol scale to give 243.8 mg (42%) of crude product. MS: exact mass calcd for C₂₅H₃₀N₃O⁺, 388.2; m/z found, 388.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 0.575 mmol scale, to give 100.0 mg (23%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₅H₃₃N₃O, 391.3; m/z found, 392.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.62 (d, J=4.4, 1H), 8.04 (m, 1H), 7.63 (d, J=7.8, 1H), 7.53 (m, 1H), 6.94 (d, J=2.4, 1H), 6.85 (m, 1H), 6.88 (br s, 1H), 4.88 (m, 1H), 4.72 (m, 1H), 4.13 (t, J=5.8, 2H), 3.88 (br s, 1H), 3.76 (m, 2H), 3.61 (d, J=12.1, 2H), 3.53 (br s, 1H), 2.98 (m, 2H), 2.84 (m, 1H), 2.35 (m, 3H), 2.26 (m, 2H), 1.97 (m, 2H), 1.82 (m, 3H), 1.57 (m, 1H).

Example 26

Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyridin-3-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.176 g (82%) of crude product after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₅H₃₃N₃O₂, 407.3; m/z found, 408.5 [M+H]⁺.

Step 2. 9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.52 mmol scale, to give 749.9 mg (70%) of crude product. MS: exact mass calcd for C₂₅H₃₀N₃O⁺, 388.2; m/z found, 388.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.77 mmol scale, to give 208.4 mg (16%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₅H₃₃N₃O, 391.3; m/z found, 392.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.91 (m, 2H), 8.51 (d, J=8.1, 1H), 8.08 (m, 1H), 6.98 (d, J=2.4, 1H), 6.89 (m, 1H), 6.73 (d, J=8.5, 1H), 4.95 (m, 1H), 4.85 (m, 1H), 4.14 (t, J=5.7, 2H), 3.94 (br s, 1H), 3.75 (m, 1H), 3.61 (d, J=11.2, 3H), 3.48 (m, 1H), 3.22 (m, 2H), 2.98 (m, 2H), 2.88 (m, 1H), 2.30 (m, 5H), 1.96 (d, J=14.6, 2H), 1.83 (m, 3H), 1.54 (m, 1H).

Example 27-(A-B)

27A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

27B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-Bromo-1-pyridin-4-yl-ethanone. To a 0° C. solution of 4-acetylpyridine (4.90 g, 41.3 mmol) and 48% HBr (7.0 mL) in acetic acid (46.0 mL) was added, dropwise over 15 min, a solution of Br₂ (2.3 mL, 45 mmol) in acetic acid (8.0 mL). After the addition was complete, the mixture was allowed to warm to rt and then was heated at 70° C. for 1 h. The mixture was cooled to 0° C. and treated with diethyl ether. The resultant white solid was isolated by vacuum filtration to give 9.90 g (87%) of the ketone as the HBr salt. MS: exact mass calcd for C₇H₆BrNO, 199.0; m/z found, 200.2 [M+H]⁺.

Step 2. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyridin-4-yl-ethanone. Prepared as described in Example 8, Step 1, on a 6.93 mmol scale, to give crude product that was taken directly to the next step.

Step 3. 9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 6.93 mmol scale to give crude product that was taken directly to the next step.

Step 4. Prepared as described in Example 17, Step 3, on a 6.93 mmol scale, to give the diastereomers in a combined yield of 2.6%.

27A: Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 3.1 mg (0.6%) as the TFA salt. MS: exact mass calcd for C₂₅H₃₃N₃O, 391.3; m/z found, 392.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.73 (br s, 2H), 7.66 (br s, 2H), 6.93 (d, J=2.5, 1H), 6.85 (dd, J=2.5, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.86 (m, 1H; obscured by solvent signal), 4.61 (m, 1H), 4.10 (5.7, 2H), 3.88 (m, 1H), 3.68 (m, 1H), 3.58 (d, J=12.0, 2H), 3.41 (m, 1H), 2.95 (m, 2H), 2.83 (m, 1H), 2.26 (m, 3H), 1.96 (d, J=14.7, 2H), 1.78 (m, 3H), 1.53 (m, 1H).

27B: Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 9.1 mg (2%) as the TFA salt. MS: exact mass calcd for C₂₅H₃₃N₃O, 391.3; m/z found, 392.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 9.03 (br s, 2H), 7.85 (br s, 2H), 6.99 (m, 3H), 4.91 (m, 1H; partially obscured by solvent signal), 4.15 (t, J=5.7, 2H), 3.88 (br s, 2H), 3.70 (m, 1H), 3.60 (d, J=12.2, 3H), 3.48 (br s, 1H), 3.32 (m, 2H; partially obscured by solvent signal), 2.97 (m, 2H), 2.82 (br m, 1H), 2.20 (m, 5H), 1.97 (d, J=14.6, 2H), 1.82 (m, 3H), 1.54 (m, 1H).

Example 28

Cis-7-(1-Isopropyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline

Step 1. 4-(3-Methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.0 g, 49.8 mmol), methyl 3-hydroxybenzoate (9.94 g, 65.3 mmol), and polymer-bound triphenylphosphine (21.5 g, 64.6 mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C. and treated with di-tert-butyl azodicarboxylate (15.0 g, 65.2 mmol). The mixture was kept at 0° C. for 1.5 h with occasional swirling. The mixture was then allowed to warm to rt and the flask clamped onto a shaker table and the mixture swirled for 4 d. The resin was filtered off and the filtrate was washed with 1 N NaOH and brine. The organic layer was dried (MgSO₄), and concentrated to give the crude product as a brown solid. Chromatographic purification (EtOAc/hexanes) gave the desired product as a colorless oil (16.58 g, 99%). ¹H NMR (acetone-d₆): 7.57 (m, 2H), 7.40 (m, 1H), 7.23 (m, 1H), 4.65 (m, 1H), 3.86 (s, 3H), 3.73 (m, 2H), 3.29 (m, 2H), 1.95 (m, 2H), 1.65 (m, 2H), 1.44 (s, 9H).

Step 2. 3-(Piperidin-4-yloxy)-benzoic acid methyl ester. A mixture of 4-(3-methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (16.5 g, 49.0 mmol) and TFA (50 mL) was stirred under a stream of nitrogen for 1 h. Evolution of gas was evident. The mixture was concentrated to provide the desired product as the TFA salt, (21.7 g, >100%). MS: exact mass calcd for C₁₃H₁₇NO₃, 235.1; m/z found, 236.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.60 (m, 2H), 7.39 (m, 1H), 7.23 (m, 1H), 5.08 (s, 4H), 4.76 (m, 1H), 3.88 (s, 3H), 3.39 (m, 2H), 3.22 (m, 2H), 2.16 (m, 2H), 2.02 (m, 2H).

Step 3. 3-(1-Isopropyl-piperidin-4-yloxy)-benzoic acid methyl ester. A mixture of 3-(piperidin-4-yloxy)-benzoic acid methyl ester (TFA salt, 21.7 g, 46.8 mmol), Et₃N (39.0 mL, 0.281 mol), and 2-iodopropane (7.1 mL, 70.2 mmol) in THF (95 mL) was heated at 55° C. for 2 d, treated with additional 2-iodopropane (4 mL, 40.1 mmol), and heated for 1 d further. The reaction mixture was diluted with Et₂O, washed with 1 N NaOH and brine, dried (Na₂CO₃), and concentrated to give a yellow oil. Chromatographic purification (EtOAc/hexanes) gave the desired product as a pale-yellow oil (8.17 g, 63%). MS: exact mass calcd for C₁₆H₂₃NO₃, 277.2; m/z found, 278.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.55 (m, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.18 (m, 1H), 4.40 (m, 1H), 3.87 (s, 3H), 2.74 (m, 3H), 2.38 (m, 2H), 1.99 (m, 2H), 1.68 (m, 2H), 1.00 (d, J=6.6, 6H).

Step 4. 4-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-1-isopropyl-piperidine: Prepared as described in Example 1, Step 4, on a 29.2 mmol scale, to give 5.92 g (71%) of the desired product as a colorless oil after column chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₁₈H₂₆N₂O, 286.2; m/z found, 287.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.41 (s, 1H), 7.31 (m, 2H), 7.01 (m, 1H), 4.40 (m, 1H), 3.96 (m, 2H), 2.95 (m, 2H), 2.78 (m, 2H), 2.71 (heptet, J=6.6, 1H), 2.43 (m, 2H), 2.01 (m, 4H), 1.76 (m, 2H), 1.07 (d, J=6.6, 6H).

Step 5. 1-Isopropyl-4-(3-pyrrolidin-2-yl-phenoxy)-piperidine. Prepared as described in Example 1, Step 5, on a 20.4 mmol scale, to give 5.79 g (99%) of the desired product as a colorless oil after column chromatography (NH₃ in MeOH/CH₂Cl₂). A small sample was purified by reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass calcd for C₁₈H₂₈N₂O, 288.2; m/z found, 289.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.41 (m, 1H), 7.12 (m, 3H), 4.63 (m, 1H), 3.6-3.3 (m, 8H), 2.45 (m, 2H), 2.24 (m, 5H), 1.95 (m, 1H), 1.40 (m, 6H).

Step 6. 2-{2-[3-(1-Isopropyl-piperidin-4-yloxy)-phenyl]-pyrrolidin-1-yl}-1-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.28 g (84%) of the desired product as a pale yellow foam after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₇H₃₆N₂O₃, 436.3; m/z found, 437.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.82 (dd, J=1.9, 7.0, 2H), 7.22 (m, 1H), 7.06 (d, J=1.3, 1H), 6.97 (d, J=7.5, 1H), 6.91 (dd, J=1.9, 7.0, 2H), 6.86 (m, 1H), 4.86 (s, 1H), 4.61 (br s, 1H), 3.96 (d, J=16.7, 1H), 3.83 (s, 3H), 3.55 (m, 2H), 3.42 (m, 2H), 3.27 (m, 2H), 3.16 (m, 2H), 2.36 (m, 1H), 2.19 (m, 3H), 2.0 (m, 3H), 1.75 (m, 1H), 1.74 (m, 1H), 1.34 (d, J=6.7, 6H).

Step 7. 9-(1-Isopropyl-piperidin-4-yloxy)-6-(4-methoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.92 mmol scale, to give 860 mg (65%) of crude product. MS: exact mass calcd for C₂₇H₃₃N₂O₂ ⁺, 417.3; m/z found, 417.5 [M]⁺.

Step 8. Prepared as described in Example 17, Step 3, on a 1.89 mmol scale, to give 28.3 mg (3%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.20 (d, J=8.2, 2H), 7.03 (m, 1H), 6.97 (d, J=8.1, 2H), 6.87 (m, 1H), 6.74 (m, 1H), 4.92 (m, 1H), 4.41 (m, 1H), 3.89 (m, 1H), 3.86 (s, 3H), 3.58 (m, 3H), 3.44 (m, 3H), 3.32 (m, 2H), 2.89 (m, 1H), 2.35 (m, 6H), 1.99 (m, 1H), 1.42 (m, 6H).

Example 29

Cis-9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 4-(3-Methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester. Prepared as described in Example 28, Step 1, on a 45.0 mmol scale, yielding 13.66 g (87%) of the desired product as a colorless oil. MS: exact mass calcd for C₁₉H₂₇NO₆, 349.2; m/z found, 372.4 [M+Na]⁺. ¹H NMR (acetone-d₆): 7.57 (d, J=7.6, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 4.10 (m, 2H), 3.90 (m, 2H), 3.86 (s, 3H), 2.79 (br s, 2H), 1.97 (m, 1H), 1.82 (m, 2H), 1.43 (s, 9H), 1.23 (m, 2H).

Step 2. 3-(Piperidin-4-ylmethoxy)-benzoic acid methyl ester. Prepared as described in Example 28, Step 2, on a 39.0 mmol scale. The crude product was diluted with in 1 N NaOH and extracted with diethyl ether. The organic layer was washed with brine, dried over Na₂CO₃, and concentrated to give the desired product as an oil that crystallized on standing (7.14 g, 73%). MS: exact mass calcd for C₁₄H₁₉NO₃, 249.1; m/z found, 250.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.66 (d, J=6.8, 1H), 7.60 (s, 1H), 7.45 (m, 1H), 7.22 (d, J=7.3, 1H), 4.98 (s, 1H), 3.98 (s, 3H), 3.92 (d, J=4.6, 2H), 3.18 (d, J=11.4, 2H), 2.72 (t, J=12.0, 2H), 2.02 (br s, 1H), 1.92 (d, J=12.4, 2H), 1.44 (m, 2H).

Step 3. 3-(1-Isopropyl-piperidin-4-ylmethoxy)-benzoic acid methyl ester. A mixture of 3-(piperidin-4-ylmethoxy)-benzoic acid methyl ester (6.82 g, 27.4 mmol), acetone (40 mL), acetic acid (1.6 mL, 27.4 mmol), and NaB(OAc)₃H (18.4 g, 86.8 mmol) in THF (110 mL) was stirred for 4.5 h. The mixture was diluted with CH₂Cl₂, washed with 1 N NaOH and brine, dried (Na₂CO₃), and concentrated to give the crude product. Chromatographic purification (EtOAc/hexanes) yielded the desired product as a pale yellow oil (6.43 g, 81%). MS: exact mass calcd for C₁₇H₂₅NO₃, 291.2; m/z found, 292.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.55 (dd, J=1.0, 7.7, 1H), 7.49 (m, 1H), 7.33 (m, 1H), 7.12 (m, 1H), 3.87 (s, 3H), 3.82 (d, J=6.2, 2H), 2.91 (d, J=11.6, 2H), 2.69 (heptet, J=6.6, 1H), 2.18 (m, 2H), 1.83 (d, J=13.2, 2H), 1.77 (m, 1H), 1.40 (m, 2H), 1.05 (d, J=6.6, 6H).

Step 4. 4-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxymethyl]-1-isopropyl-piperidine. Prepared as described in Example 1, Step 4, on a 21.8 mmol scale, to give 4.92 g (75%) of the desired product as a colorless oil after column chromatography (NH₃ in MeOH/CH₂Cl₂). A small sample was purified by reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass calcd for C₁₉H₂₈N₂O, 300.2; m/z found, 301.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.63 (m, 2H), 7.57 (m, 1H), 7.39 (m, 1H), 4.24 (t, J=7.8, 2H), 4.0 (d, J=5.8, 2H), 3.64 (m, 2H), 3.52 (m, 3H), 3.10 (m, 2H), 2.42 (quintet, J=7.9, 2H), 2.17 (m, 3H), 1.76 (m, 2H), 1.37 (m, 6H).

Step 5. 1-Isopropyl-4-(3-pyrrolidin-2-yl-phenoxymethyl)-piperidine. Prepared as described in Example 1, Step 5, on a 20.4 mmol scale, to give 5.79 g (99%) of the desired product as a colorless oil after column chromatography (NH₃ in MeOH/CH₂Cl₂). A small sample was purified by reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass calcd for C₁₉H₃₀N₂O, 302.2; m/z found, 303.5 [M+H]⁺. ¹H NMR (MeOH-d₄, TFA salt): 7.36 (m, 1H), 7.06 (m, 2H), 6.98 (m, 1H), 4.93 (s, 5H), 4.59 (m, 1H), 3.92 (d, J=5.5, 2H), 3.40 (m, 5H), 3.08 (m, 2H), 2.47 (m, 1H), 2.18 (m, 6H), 1.71 (m, 2H), 1.37 (m, 6H).

Step 6. 2-{2-[3-(1-Isopropyl-piperidin-4-ylmethoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.31 mmol scale, to give 1.04 g (70%) of the desired product as a pale yellow oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₇H₃₆N₂O₃, 450.3; m/z found, 451.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.84 (m, 2H), 7.20 (m, 1H), 7.01 (d, J=1.5, 1H), 6.96 (d, J=7.5, 1H), 6.92 (m, 2H), 6.81 (m, 1H), 4.89 (s, 1H), 3.96 (d, J=16.6, 1H), 3.86 (m, 5H), 3.46 (m, 3H), 3.29 (m, 3H), 2.80 (t, J=12.3, 2H), 2.33 (m, 1H), 2.18 (m, 1H), 2.02 (m, 4H), 1.87 (m, 1H), 1.75 (m, 1H), 1.64 (m, 2H), 1.28 (d, J=6.7, 6H).

Step 7. 9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.05 mmol scale, to give 740 mg (77%) of crude product. MS: exact mass calcd for C₂₈H₃₅N₂O₂ ⁺, 431.3; m/z found, 431.5 [M]⁺.

Step 8. Prepared as described in Example 17, Step 3, on a 1.58 mmol scale to give 102.3 mg (12%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₈H₃₈N₂O₂, 434.3; m/z found, 435.6 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.15 (d, J=8.6, 2H), 6.93 (d, J=8.8, 2H), 6.85 (d, J=2.3, 1H), 6.76 (m, 1H), 6.70 (d, J=8.7, 1H), 4.85 (m, 1H), 4.34 (m, 1H), 3.88 (m, 3H), 3.78 (s, 3H), 3.53 (m, 4H), 3.38 (m, 2H), 3.06 (t, J=11.8, 2H), 2.81 (m, 1H), 2.25 (m, 3H), 2.11 (d, J=12.2, 3H), 1.72 (m, 2H), 1.35 (d, J=6.7, 6H).

Example 30

Cis-Dimethyl-{4-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenyl}-amine

Step 1. 1-(4-Dimethylamino-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 0.93 g (77%) of the desired product as a viscous oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₈H₃₉F₃N₃O₂, 449.3; m/z found, 450.5 [M+H]⁺.

Step 2. 6-(4-Dimethylamino-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.07 mmol scale, to give 740 mg (83% crude) of the desired product. MS: exact mass calcd for C₂₈H₃₆N₃O⁺, 430.3; m/z found, 430.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.72 mmol scale, to give 87.6 mg (14%) of the desired product as the TFA salt after chromatography (NH₃ in MeOH/CH₂Cl₂) and HPLC. MS: exact mass calcd for C₂₈H₃₉N₃O, 433.3; m/z found, 434.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.19 (d, J=8.6, 2H), 7.03 (d, J=8.7, 2H), 6.95 (m, 1H), 6.80 (m, 1H), 6.72 (d, J=8.7, 1H), 4.94 (m, 1H), 4.49 (m, 1H), 4.15 (t, J=5.9, 2H), 3.98 (br s, 1H), 3.68 (m, 3H), 3.40 (m, 4H), 3.04 (s, 6H), 2.91 (m, 1H), 2.33 (m, 6H), 2.06 (m, 5H), 1.82 (m, 1H), 1.53 (m, 1H).

Example 31

Cis-9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-m-tolyl-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 610 mg (54%) of the desired product as an orange oil after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₇H₃₆N₂O₂, 420.3; m/z found, 421.5 [M+H]⁺.

Step 2. 9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 1.45 mmol scale, to give 560 mg (96%) of crude product. MS: exact mass calcd for C₂₇H₃₃N₂O⁺, 401.3; m/z found, 401.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 0.25 mmol scale, to give 3.1 mg (1.3%) of the desired product as the TFA salt after chromatography (NH₃ in MeOH/CH₂Cl₂) and HPLC. MS: exact mass calcd for C₂₇H₃₆N₂O, 404.3; m/z found, 405.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.14 (m, 1H), 7.01 (m, 2H), 6.95 (d, J=7.3, 1H), 6.80 (s, 1H), 6.64 (d, J=8.7, 1H), 6.57 (d, J=8.6, 1H), 4.47 (br s, 1H), 4.32 (m, 1H), 4.00 (m, 2H), 3.52 (br s, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 3.13 (m, 4H), 2.70 (m, 4H), 2.33 (m, 1H), 2.17 (m, 7H), 1.78 (m, 5H), 1.53 (m, 1H).

Example 32

Cis-6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.46 mmol scale, to give 1.0 g (54%) of the desired product as an orange semi-solid after chromatography (NH₃ in MeOH/CH₂Cl₂). MS: exact mass calcd for C₂₆H₃₃ ¹N₂O₂, 532.2; m/z found, 533.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.20 (m, 1H), 7.82 (m, 2H), 7.24 (t, J=7.9, 1H), 7.12 (t, J=7.9, 1H), 6.97 (d, J=7.6, 1H), 6.93 (m, 1H), 6.78 (m, 1H), 3.97 (m, 2H), 3.42 (t, J=8.7, 1H), 3.35 (m, 2H), 2.61 (m, 6H), 2.34 (m, 1H), 2.18 (m, 1H), 2.05 (m, 4H), 1.85 (m, 2H), 1.68 (m, 4h), 1.48 (m, 2H).

Step 2. 6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 1.90 mmol scale, to give 800 mg (82%) of crude product. MS: exact mass calcd for C₂₆H₃₀IN₂O⁺, 513.1; m/z found, 513.4 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.54 mmol scale, to give 165 mg (14%) of the desired product after chromatography and HPLC. MS: exact mass calcd for C₂₆H₃₃IN₂O, 516.2; m/z found, 517.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.76 (d, J=7.8, 1H), 7.69 (s, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 6.97 (m, 1H), 6.81 (m, 1H), 6.67 (d, J=8.7, 1H), 4.91 (m, 1H), 4.59 (m, 1H), 4.14 (m, 2H), 3.71 (br s, 1H), 3.66 (m, 3H), 3.53 (m, 1H), 3.42 (m, 1H), 3.32 (br s, 2H), 2.91 (m, 3H), 2.34 (m, 5H), 1.95 (m, 5H), 1.51 (m, 1H).

Example 33

Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh₃)₂Cl₂ (6.0 mg, 0.008 mmol), CuI (2.0 mg, 0.008 mmol), PPh₃ (4.0 mg, 0.016 mmol), Et₂NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C₃₁H₄₂N₂OSi, 486.3; m/z found, 487.6 [M+H]⁺. ¹H NMR (acetone-d₆): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).

Example 34

Cis-6-(3-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

A solution of cis-9-(3-piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 33, 40.0 mg, 0.082 mmol) and K₂CO₃ (2.0 mg, 0.008 mmol) in MeOH (4.1 mL, 0.2 M) was stirred for 2 h at rt. The crude reaction mixture was purified directly after filtration by reverse-phase HPLC to give 19.0 mg (36%) of the desired product as a TFA salt. MS: exact mass calcd for C₂₈H₃₄N₂O, 414.3; m/z found, 415.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.45 (m, 4H), 6.96 (m, 1H), 6.79 (dd, J=3.2, 10.9, 1H), 6.64 (d, J=10.9, 1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.12 (t, J=7.5, 2H), 3.93 (m, 1H), 3.66 (m, 4H), 3.51 (m, 1H), 3.39 (m, 1H), 3.31 (m, 2H), 2.93 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.51 (m, 1H).

Example 35-(A-B)

35A: Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

35B: Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.08 mmol scale. The crude product was used without purification in the next step. MS: exact mass calcd for C₂₆H₃₃IN₂O₂, 532.2; m/z found, 533.4 [M+H]⁺.

Step 2. 6-(4-Iodo-phenyl)-9-(3-piperidin-1-v1-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, to give 3.5 g (>100%) of crude product. MS: exact mass calcd for C₂₆H₃₀IN₂O⁺, 513.1; m/z found, 513.4 [M]⁺.

Step 3. Performed as described in Example 17, Step 3, to give a combined yield of 20% (over three steps) of two diastereomers.

35A: Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 248.0 mg (13% over 3 steps) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃IN₂O, 516.46; m/z found, 517.4 [M+H]⁺. ¹H NMR (acetone-d₆): 13.46 (br s, 1H), 11.49 (br s, 1H), 7.89 (d, J=8.3, 2H), 7.12 (d, J=11.6, 2H), 6.96 (m, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=11.2, 1H), 4.91 (m, 1H), 4.59 (dd, J=4.6, 12.1, 1H), 4.14 (t, J=6.0, 2H), 3.96 (m, 1H), 3.69 (m, 3H), 3.41 (m, 4H), 3.00 (m, 2H), 2.91 (m, 1H), 2.33 (m, 5H), 1.91 (m, 4H), 1.80 (m, 1H), 1.53 (m, 1H).

35B: Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 138 mg (7.3% over 3 steps) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃IN₂O, 516.46; m/z found, 517.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.74 (d, J=8.2, 2H), 7.09 (d, J=8.3, 2H), 6.98 (m, 1H), 6.80 (m, 2H), 5.15 (br s, 1H), 4.60 (m, 1H), 4.17 (m, 2H), 3.63 (m, 6H), 3.41 (m, 2H), 2.92 (m, 2H), 2.77 (br s, 1H), 2.32 (m, 2H), 2.20 (m, 2H), 1.92 (m, 6H), 1.54 (m, 1H).

Example 36

Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trimethylsilanylethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Performed as described in Example 33, on a 0.27 mmol scale, to yield 131.0 mg (77%) of the desired product as the TFA salt. MS: exact mass calcd for C₃₁H₄₂N₂OSi, 486.3; m/z found, 487.6 [M+H]⁺. ¹H NMR (acetone-d₆): 7.32 (m, 2H), 7.26 (m, 2H), 6.78 (d, J=8.5, 1H), 6.72 (m, 1H), 6.68 (m, 1H), 4.12 (m, 1H), 4.01 (m, 2H), 3.18 (m, 1H), 3.05 (m, 1H), 2.93 (m, 1H), 2.79 (m, 2H), 2.37 (m, 7H), 1.89 (m, 4H), 1.73 (m, 1H), 1.53 (m, 4H), 1.41 (m, 2H), 0.23 (s, 9H).

Example 37

Cis-6-(4-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Prepared as described in Example 34, on a 0.18 mmol scale, to yield 43.0 mg (57%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₈H₃₄N₂O, 414.3; m/z found, 415.5 [M+H]⁺. ¹H NMR (acetone-d₆): 7.43 (d, J=8.3, 2H), 7.34 (d, J=8.2, 2H), 6.88 (d, J=9.8, 1H), 6.79 (m, 1H), 6.75 (m, 1H), 4.18 (m, 1H), 4.07 (m, 2H), 3.62 (s, 1H), 3.24 (m, 1H), 3.13 (m, 1H), 3.00 (m, 1H), 2.93 (m, 1H), 2.45 (m, 8H), 1.95 (m, 4H), 1.82 (1H), 1.59 (m, 4H), 1.47 (m, 2H).

Example 38

Cis-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 3-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-benzoic acid methyl ester. Prepared as described in Example 1, Step 1, on a 0.330 mol scale, using (3-bromopropoxy)-tert-butyldimethylsilane, to give 92.3 g (86%) of the desired product after vacuum distillation (bp 177° C.@1 torr). MS: exact mass calcd for C₁₇H₂₈O₄Si, 324.2; m/z found, 325.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.56 (m, 1H), 7.52 (m, 1H), 7.40 (m, 1H), 7.18 (m, 1H), 4.14 (t, J=6.0, 2H), 3.86 (s, 3H), 3.84 (t, J=6.0, 2H), 1.98 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H).

Step 2. 3-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-propan-1-ol. Prepared as described in Example 1, Step 4, on 0.284 mol scale, to give 33.0 g (52%) of the desired product as a pale-yellow solid after filtering through a plug of silica gel and distilling with a Kugelrohr apparatus. The silyl protecting group was removed during the reaction. MS: exact mass calcd for C₁₃H₁₇NO₂, 219.1; m/z found, 220.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.38 (s, 1H), 7.32 (m, 2H), 7.02 (m, 1H), 4.99 (s, 1H), 4.10 (t, J=6.0, 2H), 3.96 (t, J=7.0, 2H), 3.76 (t, J=6.0, 2H), 2.92 (t, J=8.0, 2H), 1.99 (m, 4H).

Step 3. 3-(3-Pyrrolidin-2-yl-phenoxy)-propan-1-ol. Prepared as described in Example 1, Step 5, on a 0.149 mol scale, to give 27.2 g (82%) of the desired product as a colorless oil. MS: exact mass calcd for C₁₃H₁₉NO₂, 221.1; m/z found, 222.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.21 (m, 1H), 6.92 (d, J=1.5, 1H), 6.90 (d, J=7.5, 1H), 6.80 (dd, J=2.5, 8.0, 1H), 4.89 (s, 2H), 4.06 (t, J=6.5, 2H), 3.98 (t, J=9.0, 1H), 3.73 (t, J=6.0, 2H), 3.15 (m, 1H), 2.91 (m, 1H), 2.18 (m, 1H), 1.96 (m, 2H), 1.87 (m, 2H), 1.69 (m, 1H).

Step 4. 2-{2-[3-(3-Hydroxy-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 82.2 mmol scale, to give 36.59 g (>100%) of the desired product after column chromatography (EtOAc/hexanes). MS: exact mass calcd for C₂₂H₂₇NO₄, 369.2; m/z found, 370.4 [M+H]⁺. ¹H NMR (acetone-d₆): 7.87 (m, 2H), 7.22 (m, 1H), 7.03 (m, 1H), 6.94 (m, 3H), 6.81 (m, 1H), 4.09 (m, 2H), 4.02 (d, J=19.0, 1H), 3.84 (s, 3H), 3.74 (t, J=8.0, 2H), 3.47 (t, J=10.0, 1H), 3.28 (m, 2H), 2.36 (m, 1H), 2.15 (m, 1H), 1.96 (m, 2H), 1.84 (m, 2H), 1.68 (m, 1H).

Step 5. 9-(3-Hydroxy-propoxy)-6-(4-methoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on an 82.2 mmol scale, to give 30.09 g (95%) of crude product. The product was taken on to the next step without purification. MS: exact mass calcd for C₂₂H₂₄NO₃ ⁺, 350.2; m/z found, 350.4 [M+H]⁺.

Step 6. Cis-3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propan-1-ol. Prepared as described in Example 17, Step 3, on 78.1 mmol scale, to give 10.09 g (37%) of the desired product after column chromatography (EtOAc) and reverse-phase HPLC. The product was characterized as the TFA salt. MS: exact mass calcd for C₂₂H₂₇NO₃, 353.2; m/z found, 354.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.16 (d, J=8.5, 2H), 6.93 (d, J=9.0, 2H), 6.85 (d, J=2.5, 1H), 6.76 (m, 1H), 6.69 (d, J=8.5, 1H), 4.84 (m, 1H), 4.33 (m, 1H), 4.06 (t, J=6.5, 2H), 3.87 (m, 1H), 3.77 (s, 3H), 3.71 (t, J=6.3, 2H), 3.55 (m, 1H), 3.37 (m, 2H), 2.81 (m, 1H), 2.25 (m, 3H), 1.96 (m, 2H).

Step 7. Cis-Methanesulfonic acid 3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl ester. A solution of cis-3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propan-1-ol (28.5 mmol) and Hunig's base (3 equiv.) in THF (0.2 M) was cooled to 0° C. and treated with methanesulfonyl chloride (2.1 equiv.). The mixture was stirred at 0° C. for 1 h. The mixture was then diluted with methylene chloride, washed with 1 N NaOH and brine, dried (Na₂CO₃), and concentrated to give the crude product, which was immediately taken on to the next step. MS: exact mass calcd for C₂₂H₂₇NO₄, 431.2; m/z found, 432.4 [M+H]⁺.

Step 8. A mixture of crude cis-methanesulfonic acid 3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl ester (28.5 mmol), Na₂CO₃ (4 equiv.), KI (0.5 equiv.), and morpholine (7.52 mmol, 10 equiv.) in ethanol (0.2 M) was heated to 50° C. overnight. The mixture was cooled to rt, diluted with CH₂Cl₂, and filtered. The filtrate was concentrated to give the crude product. Column chromatography (NH₃ in MeOH/CH₂Cl₂) followed by HPLC give the desired product (8.19 g, 68%). The enantiomers were separated using a Chiralcel AD-h column on a SFC HPLC eluting with IPA/MeOH with 0.2% DEA. MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.3; m/z found, 423.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.06 (d, J=8.5, 2H), 6.82 (d, J=8.5, 2H), 6.70 (d, J=2.5, 1H), 6.67 (d, J=8.5, 1H), 6.61 (dd, J=2.5, 8.5 1 H), 4.08 (dd, J=8.5, 5.5, 1H), 3.97 (t, J=6.5, 2H), 3.79 (m, 1H), 3.74 (s, 3H), 3.67 (m, 4H), 2.91 (m, 3H), 2.78 (dd, J=5.0, 11.2, 1H), 2.47 (m, 6H), 2.34 (m, 1H), 1.91 (m, 5H).

Example 39-(A-C)

39A: Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

39B: Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

39C: 6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 5-(3-Methoxy-phenyl)-3,4-dihydro-2H-pyrrole. Prepared as described in Example 1, Step 4, on a 0.24 mol scale, using 3 N HCl in place of 12 N HCl during the workup procedure, to give 37.8 g of the desired product. MS: exact mass calcd for C₁₁H₁₃NO, 175.1; m/z found, 176.1 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.36 (m, 3H), 7.03 (m, 1H), 3.94 (m, J=7.4, 2H), 3.79 (s, 3H), 2.89 (t, J=8.0, 2H), 1.93 (m, 2H).

Step 2. 2-(3-Methoxy-phenyl)-pyrrolidine. A solution of 5-(3-methoxy-phenyl)-3,4-dihydro-2H-pyrrole (0.21 mol) in absolute ethanol (1.2 M) was treated portionwise with NaBH₄ (1.0 equiv.). The resultant mixture was stirred at rt overnight. The mixture was cooled to 0° C. and slowly quenched with 1 N HCl. The mixture was acidified to a pH of 1 with 3 N HCl and was stirred at rt for 45 min. The resulting mixture was again cooled to 0° C., and was treated with 1 N NaOH until basic. The aqueous mixture was extracted with CH₂Cl₂ (×3). The combined extracts were washed with brine, dried (MgSO₄), filtered and concentrated to give the crude product. Chromatography (EtOAc/hexanes) gave 37.0 g (99%) of the desired product. MS: exact mass calcd for C₁₁H₁₅NO, 177.1; m/z found, 178.1 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.23 (m, 1H), 7.05 (m, 1H), 6.98 (d, J=7.6, 1H), 6.79 (dd, J=2.8, 8.0, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 3.15 (m, 1H), 3.03 (m, 1H), 2.19 (m, 1H), 1.86 (m, 2H), 1.69 (m, 1H).

Step 3. 2-Hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-2-(4-methylsulfanyl-phenyl)-ethanone. A mixture of 2-(3-methoxy-phenyl)-pyrrolidine (59.2 mmol), hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.05 equiv.), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.2 equiv.), and Hunig's base (1.5 equiv.) in CH₂Cl₂ (0.2 M) was stirred at rt overnight under nitrogen. The reaction mixture was filtered to remove a white precipitate and the filtrate was washed with 1 N HCl, water, 1 N NaOH, water, and brine, dried (MgSO₄), and concentrated to give the crude product as a mixture of diastereomers. The crude product was purified by normal phase column chromatography (EtOAc/hexanes) to give 29.6 g (37%) of the product as a mixture of diastereomers. MS: exact mass calcd for C₂₀H₂₃NO₃S, 357.1; m/z found, 358.1 [M+H]⁺.

Step 4. 9-Methoxy-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. A solution of amide from Step 1 (33.3 mmol) and polyphosphoric acid (5 g/g amide) was heated at 105° C. under nitrogen until the starting material was consumed (2 h). The reaction mixture was poured into water and extracted with CH₂Cl₂ (×2). The combined extracts were washed with satd. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated to provide the crude product. The crude material was purified by chromatography to give 9.3 g (82%) of the product as a mixture of diastereomers and regioisomers. MS: exact mass calcd for C₂₀H₂₁NO₂S, 339.1; m/z found, 340.0 [M+H]⁺.

Step 5. 9-Hydroxy-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. A solution of amino-ketone (Step 2; 0.15 mmol, 1.0 equiv.) in CH₂Cl₂ (0.5 M) was treated dropwise with BBr₃ (5.0 equiv.). The reaction mixture was stirred at rt until complete. The reaction was cooled to 0° C. and quenched with water. The crude mixture was sonicated, extracted with CH₂Cl₂, washed with brine, dried (MgSO₄), and concentrated to give 50 mg (>100%) of the crude product as a mixture of diastereomers and regioisomers. MS: exact mass calcd for C₁₉H₁₉NO₂S, 325.1; m/z found, 326.1 [M+H]⁺.

Step 6. 9-(3-Chloro-propoxy)-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. Prepared as described in Example 1, Step 1, on a 1.23 mmol scale, to give 330 mg (67%) of the crude product as a mixture of diastereomers and regioisomers after normal phase column chromatography (EtOAc/hexanes). MS: exact mass calcd for C₂₂H₂₄ClNO₂S, 401.1; m/z found, 402.0 [M+H]⁺.

Step 7. 6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. A solution of amino-ketone (Step 4; 0.82 mmol), Na₂CO₃ (1.5 equiv.), KI (0.05 equiv.), and piperidine (1.5 equiv.) in n-butanol (0.3 M) was heated at 100° C. overnight. The reaction mixture was cooled to rt, diluted with CH₂Cl₂, and filtered. The filtrate was concentrated to give the crude product (350 mg, 95%) as a mixture of diastereomers and regioisomers. MS: exact mass calcd for C₂₇H₃₄N₂O₂S, 450.2; m/z found, 451.2 [M+H]⁺.

Step 8. To a 0° C. solution of BH₃.THF (1 M in THF, 2.5 equiv.) was added a solution of amino-ketone (Step 5, 0.75 mmol, 1 equiv.) in THF (2 M) and the resulting solution was heated at reflux for 1 h. The mixture was cooled to rt, quenched with water, and acidified with 12 N HCl. The THF was removed in vacuo and the aqueous mixture was heated at reflux for 15 min. The reaction mixture was again cooled to rt, made basic with 3 N NaOH, and extracted with CH₂Cl₂. The organic extract was washed with brine, dried (MgSO₄), and concentrated to give the crude products as a mixture (29%). The products were purified by reverse-phase HPLC.

39A: Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 26.0 mg (5%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂OS, 436.3; m/z found, 437.2 [M+H]⁺. ¹H NMR (acetone-d₆): 7.30 (d, J=8.4, 2H), 7.23 (d, J=8.2, 2H), 6.95 (m, 1H), 6.78 (m, 1H), 6.67 (d, J=8.6, 1H), 4.89 (m, 1H), 4.54 (m, 1H), 4.13 (t, J=6.0, 2H), 3.93 (m, 1H), 3.64 (m, 2H), 3.39 (m, 2H), 3.29 (m, 2H), 3.15 (m, 2H), 2.91 (m, 3H), 2.51 (s, 3H), 2.29 (m, 3H), 2.23 (m, 1H), 1.92 (m, 4H), 1.79 (m, 1H), 1.47 (m, 1H), 1.32 (m, 2H).

39B: Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 82.0 mg (16%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂OS, 436.3; m/z found, 437.2 [M+H]⁺. ¹H NMR (acetone-d₆): 13.02 (br s, 1H), 11.64 (br s, 1H), 7.26 (d, J=10.4, 2H), 7.19 (d, J=10.4, 2H), 6.98 (br s, 1H), 6.83 (m, 2H), 5.65 (br s, 2H), 5.07 (br s, 1H), 4.52 (br s, 1H), 4.15 (t, J=5.6, 2H), 3.82 (m, 1H), 3.65 (m, 3H), 3.57 (m, 1H), 3.34 (m, 2H), 2H), 2.99 (m, 2H), 2.74 (m, 1H), 2.49 (s, 3H), 2.32 (m, 2H), 2.20 (m, 2H), 1.92 (m, 4H), 1.84 (m, 1H), 1.52 (m, 1H).

39C: 6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 39.0 mg (8%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂OS, 436.3; m/z found, 437.2 [M+H]⁺. ¹H NMR (acetone-d₆): 11.85 (br s, 1H), 11.31 (br s, 1H), 7.41 (m, 1H), 7.20 (d, J=9.7, 2H), 7.07 (m, 3H), 6.97 (d, 10.3, 1H), 5.13 (br s, 1H), 4.75 (s, 1H), 4.13 (m, 1H), 3.85 (m, 4H), 3.36 (m, 3H), 2.86 (m, 1H), 2.62 (m, 2H), 2.51 (m, 1H), 2.46 (s, 3H), 2.23 (m, 3H), 2.06 (m, 2H), 1.80 (m, 6H), 1.47 (m, 1H).

Example 40

Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-(4-Bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-ethanone. A solution of 2-(3-methoxy-phenyl)-pyrrolidine (16.9 mmol, 1.0 equiv.) and hydroxy-(4-bromo-phenyl)-acetic acid (1.0 equiv.) in xylenes (0.2 M) was heated at reflux for 3 d under nitrogen. The bulk of the xylenes was removed by distillation and the residue was purified by chromatography (EtOAc/hexanes) to give the desired product as a mixture of diastereomers (3.66 g, 55%). MS: exact mass calcd for C₁₉H₂₀BrNO₃, 389.1; m/z found, 390.0 [M+H]⁺, 392.0 [M+H]⁺.

Step 2. A solution of 2-(4-bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-ethanone (3.6 g, 9.2 mmol) and PPA (15.0 g) was heated at 100° C. for 1 h. The mixture was cooled to rt, poured into water, and extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated. Purification by normal phase column chromatography (EtOAc/hexanes) gave 87% combined yield of four isomeric products.

Cis-6-(4-Bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 500 mg (15%). MS: exact mass calcd for C₁₉H₁₈BrNO₂, 371.1 m/z found, 372.0 [M+H]⁺, 374.0 [M+H]⁺. ¹H NMR (acetone-d₆): 7.62 (d, J=8.4, 2H), 7.22 (d, J=8.4, 2H), 6.95 (m, 1H), 6.80 (dd, J=2.6, 8.6, 1H), 6.48 (m, 1H), 4.78 (m, 1H), 4.73 (s, 1H), 3.84 (s, 3H), 3.63 (m, 1H), 3.52 (m, 1H), 2.82 (m, 1H), 2.20 (m, 1H), 2.08 (m, 2H).

Trans-6-(4-Bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 170.0 mg (6%). MS: exact mass calcd for C₁₉H₁₈BrNO₂, 371.1; m/z found, 372.0 [M+H]⁺, 374.0 [M+H]⁺. ¹H NMR (acetone-d₆): 7.41 (d, J=8.5, 2H), 7.22 (d, J=9.3, 1H), 7.08, (d, J=8.2, 2H), 6.95 (m, 2H), 4.77 (s, 1H), 4.57 (m, 1H), 3.84 (s, 3H), 3.48 (m, 2H), 2.69 (m, 1H), 2.04 (m, 1H), 1.86 (m, 2H).

Cis-6-(4-Bromo-phenyl)-7-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 420 mg (14%). MS: exact mass calcd for C₁₉H₁₈BrNO₂, 371.1; m/z found, 372.0 [M+H]⁺, 374.0 [M+H]⁺. ¹H NMR (acetone-d₆): 7.49 (d, J=8.5, 2H), 7.38 (m, 1H), 7.09 (d, J=8.5, J=2H), 7.06 (d, J=7.8, 1H), 6.88 (d, J=8.2, 1H), 4.74 (m, 1H), 4.70 (m, 1H), 3.82 (m, 1H), 3.58 (s, 3H), 3.36 (m, 1H), 2.73 (m, 1H), 2.10 (m, 2H), 1.87 (m, 1H).

Trans-6-(4-Bromo-phenyl)-7-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. The material obtained from the purification by normal phase column chromatography was recrystallized from acetone to give 48.3 mg (2%) of the desired product as white crystals. ¹H NMR (acetone-d₆): 7.45 (d, J=8.5, 2H), 7.37 (m, 1H), 7.02 (m, 3H), 6.96 (m, 1H), 4.89 (s, 1H), 4.58 (m, 1H), 3.74 (s, 3H), 3.41 (m, 2H), 2.65 (m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.73 (m, 1H).

Step 3. Cis-6-(4-Bromo-phenyl)-9-hydroxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. Prepared from cis-6-(4-bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one (3.49 mmol) as described in Example 39, Step 5. The crude mixture was sonicated and extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO₄), and concentrated to give 1.08 g (86%) of crude product. A small amount was purified by reverse phase HPLC to give the product as the TFA salt. MS: exact mass calcd for C₁₈H₁₆BrNO₂, 357.0; m/z found, 358.0 [M+H]⁺, 360.0 [M+H]⁺. ¹H NMR (acetone-d₆): 7.55 (d, J=8.4, 2H), 7.16 (d, J=8.4, 2H), 6.79 (m, 1H), 6.64 (dd, J=2.4, 8.5, 1H), 6.31 (m, 1H), 4.70 (m, 1H), 4.64 (s, 1H), 3.58 (m, 1H), 3.44 (m, 2H), 2.70 (m, 1H), 2.14 (m, 1H), 2.09 (m, 1H), 1.97 (m, 1H).

Step 4. Cis-6-(4-Bromo-phenyl)-9-(3-chloro-propoxy)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. Prepared as described in Example 39, Step 6, on a 0.56 mmol scale, to give 205 mg (84%) of the desired product. MS: exact mass calcd for C₂₁H₂₁BrClNO₂, 433.0; m/z found, 434.0 [M+H]⁺, 436.0 [M+H]⁺. ¹H NMR (acetone-d₆): 7.27 (d, J=8.5, 2H), 7.09 (m, 1H), 6.95 (d, J=8.2, 2H), 6.82 (m, 2H), 4.58 (s, 1H), 4.42 (m, 1H), 4.04 (t, J=6.0, 2H), 3.66 (t, J=6.5, 2H), 3.32 (m, 2H), 2.56 (m, 1H), 2.10 (m, 2H), 1.92 (m, 1H), 1.81 (m, 1H), 1.70 (m, 1H).

Step 5. Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. Prepared as described in Example 39, Step 7, on a 0.46 mmol scale, to give 190 mg (86%) of the desired product. MS: exact mass calcd for C₂₆H₃₁BrN₂O₂, 482.2; m/z found, 483.1 [M+H]⁺, 485.1 [M+H]⁺. ¹H NMR (acetone-d₆): 7.46 (d, J=8.5, 2H), 7.25 (d, J=8.2, 1H), 7.10 (d, J=7.0, 2H), 6.97 (m, 2H), 4.76 (s, 1H), 4.59 (m, 1H), 4.12 (t, J=6.5, 2H), 3.49 (m, 2H), 2.85 (m, 2H), 2.74 (m, 1H), 2.45 (t, J=7.0, 2H), 2.39 (m, 4H), 1.94 (3H), 1.57 (m, 4H), 1.39 (m, 2H).

Step 6. Prepared as described in Example 39, Step 8, on a 0.93 mmol scale, to give 88.0 mg (14%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₆H₃₃BrN₂O, 468.2; m/z found, 469.1 [M+H]⁺, 471.1 [M+H]⁺. ¹H NMR (acetone-d₆): 7.55 (d, J=8.4, 2H), 7.22 (d, J=8.4, 2H), 6.99 (br s, 1H), 6.85 (m, 2H), 5.15 (br s, 1H), 4.70 (m, 3H), 4.16 (m, 2H), 3.84 (br s, 1H), 3.66 (m, 3H), 3.58 (m, 1H), 3.36 (m, 2H), 3.00 (m, 2H), 2.77 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H), 1.92 (m, 4H), 1.85 (m, 1H), 1.53 (m, 1H).

Example 41-(A-B)

41A: Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile

41B: Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile

To a sealed tube reaction vessel were added cis-6-(4-bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (0.21 mmol), CuCN (5.2 equiv.), and DMF (1.7 M). The tube was purged with nitrogen, sealed, and heated at 150° C. overnight. The reaction mixture was cooled to rt, diluted with aqueous NaCN, and extracted with diethyl ether. The organic layer was washed with water, satd. aq. NaHCO₃, and brine, dried (Na₂CO₃), and concentrated to give the crude product. Chromatographic purification (NH₃ in MeOH/CH₂Cl₂) followed by reverse-phase HPLC gave the desired product as a mixture with the 6-trans isomer (7% combined yield).

41A: Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile. 5.2 mg (4%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃N₃O, 415.3; m/z found, 416.2 [M+H]⁺. ¹H NMR (acetone-d₆): 7.74 (d, J=8.1, 2H), 7.46 (d, J=8.1, 2H), 7.00 (m, 1H), 6.85 (m, 2H), 6.80 (d, J=8.6, 1H), 5.07 (br s, 1H), 4.74 (m, 1H), 4.16 (m, 2H), 3.71 (m, 1H), 3.62 (m, 2H), 3.50 (m, 4H), 3.30 (m, 2H), 2.94 (m, 2H), 2.77 (m, 1H), 2.32 (m, 2H), 2.19 (m, 1H), 2.10 (m, 1H), 1.94 (m, 3H), 1.79 (m, 1H), 1.42 (m, 1H).

41B: Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile. 4.6 mg (3%) as the TFA salt. MS: exact mass calcd for C₂₇H₃₃N₃O, 415.3; m/z found, 416.2 [M+H]⁺. ¹H NMR (acetone-d₆): 7.82 (d, J=8.2, 2H), 7.54 (d, J=8.0, 2H), 7.02 (s, 1H), 6.79 (dd, J=2.1, 8.7, 1H), 6.62 (d, J=8.7, 1H), 4.91 (m, 1H), 4.74 (m, 1H), 4.13 (m, 2H), 3.93 (m, 1H), 3.70 (m, 1H), 3.61 (m, 3H), 3.50 (t, J=11.7, 2H), 3.37 (m, 4H), 3.29 (m, 8H), 2.93 (m, 3H).

Example 42

Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-(4-Bromo-benzylidene)-malonic acid diethyl ester. A mixture of 4-bromobenzaldehyde (118.3 g, 0.639 mol), diethyl malonate (105.5 mL, 0.6243 mol), and p-toluic acid (9.40 g, 62.6 mmol), in toluene (220 mL) was stirred under nitrogen until homogeneous and then was treated with piperidine (7.50 mL, 75.8 mmol). The flask was fitted with a Dean-Stark trap and a condenser and was heated at between 128-135° C. overnight. The mixture was diluted with toluene, washed with 10% aq. HCl, 1 N NaOH, and brine (×2). The organic layer was dried (MgSO₄) and concentrated to give the crude product as a pale-red oil. Vacuum distillation (bp=159° C.@1 torr) of the crude material yielded 142.1 g (70%) of the desired product as a pale-yellow oil. ¹H NMR (acetone-d₆): 7.67 (d, J=2.9, 1H), 7.62 (br s, 2H), 7.47 (br s, 2H), 4.29 (m, 4H), 1.26 (m, 6H).

Step 2. 2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid diethyl ester. A 0° C. solution of 3-methoxyphenyl magnesium bromide (1 M in THF; 414 mL, 0.414 mol) was treated with a solution of 2-(4-bromo-benzylidene)-malonic acid dimethyl ester (114.7 g, 0.3506 mol) in diethyl ether (250 mL), via cannula, over the course of 18 min. The mixture was stirred at 0° C. for 1 h and then was allowed to warm to rt. After 2 h, the reaction was quenched with satd. aq. NH₄Cl, and extracted with diethyl ether. The organic layer was washed with satd. aq. NH₄Cl and brine, dried (MgSO₄), and concentrated to give the crude product as a yellow oil (163.5 g, >100%). The bulk of the crude product was taken on to the next step without purification, but a small portion was purified by normal phase column chromatography (EtOAc/hexanes) for characterization. MS: exact mass calcd for C₂₁H₂₃BrO₅, 434.1; m/z found, 457.0 [M+Na]⁺, 459.0 [M+Na]⁺. ¹H NMR (acetone-d₆): 7.42 (m, 4H), 7.17 (d, J=7.9, 1H), 6.98 (m, 2H), 6.35 (m, 1H), 4.67 (d, J=12.3, 1H), 4.47 (d, J=12.2, 1H), 3.98 (m, 4H), 3.95 (s, 3H), 1.00 (m, 6H).

Step 3. 2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid. A mixture of crude 2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid diethyl ester (131.3 g, est. 0.3016 mol) in 150 mL hot ethanol was treated with a solution of KOH (85%; 99.6 g, 1.51 mol) in water (301 mL). The mixture was heated overnight at 105° C. and then was allowed to cool to rt. The mixture was diluted with water and extracted with diethyl ether (500 mL, ×3). The aqueous phase was acidified with 12 N HCl until the pH=1 and was extracted with diethyl ether (500 mL, ×3). The latter organic extracts were combined, dried (Na₂CO₃), and concentrated to give 107.97 g of a white-grey solid. The crude product was divided into two equal portions and each was suspended in 700 mL toluene. The toluene suspensions were heated at 105° C. for 3 h and then allowed to slowly cool to rt. The white solid was filtered off, rinsed with toluene, the portions combined and dried under high vacuum to give 68.8 g (60%) of the desired product as a white solid. MS (ESI, negative ionization): exact mass calcd for C₁₇H₁₅BrO₅, 378.0; m/z found, 377.9 [M−H]⁻, 379.9 [M−H]⁻. ¹H NMR (DMSO-d₆): 12.68 (br s, 2H), 7.41 (m, 4H), 7.15 (m, 1H), 6.97 (m, 2H), 6.70 (m, 1H), 4.52 (d, J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.69 (s, 3H).

Step 4. 3-(4-Bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid. To a 1-L round bottomed flask was added 79.9 g (0.211 mol) 2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid, the flask fitted with a septum, and the system subjected to a continuous stream of nitrogen (nitrogen line into septum and a needle as a bleed). The flask was then heated slowly in an oil bath to 160° C. for 2 h. Gas evolution was evident beginning at 140° C. The mixture was allowed to cool to rt to give 70.1 g (99%) of the desired product as a white solid. MS (ESI, negative ionization): exact mass calcd for C₁₆H₁₅BrO₃, 334.0; m/z found, 333.0 [M−H]⁻, 335.0 [M−H]⁻. ¹H NMR (DMSO-d₆): 12.14 (br s, 1H), 7.42 (dd, J=1.8, 6.6, 2H), 7.28 (m, 2H), 7.17 (m, 1H), 6.88 (m, 2H), 6.73 (m, 1H), 4.38 (t, J=7.9, 1H), 3.70 (s, 3H), 3.00 (dd, J=3.6, 8.0, 2H).

Step 5. [2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester. A mixture of 3-(4-bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid (24.99 g, 74.55 mmol), triethylamine (12.5 mL, 89.5 mmol) and diphenylphosphoryl azide (17.0 mL, 78.3 mmol) in tert-butanol (250 mL) was heated at 85° C. overnight. The reaction mixture was then concentrated and the residue was purified by normal phase column chromatography (EtOAc/hexanes) to give 24.19 g (80%) of the desired product as a viscous colorless oil. MS: exact mass calcd for C₂₀H₂₄BrNO₃, 405.1; m/z found, 428.1 [M+Na]⁺, 430.1 [M+Na]⁺. ¹H NMR (acetone-d₆): 7.45 (d, J=8.4, 2H), 7.27 (d, J=8.4, 2H), 7.20 (m, 1H), 6.86 (m, 2H), 6.76 (dd, J=1.9, 7.8, 1H), 5.96 (br s, 1H), 4.25 (t, J=7.9, 1H), 3.76 (s, 3H), 3.70 (m, 1H), 1.34 (s, 9H).

Step 6. 2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine. Prepared as described in Example 29, Step 2, on a 59.5 mmol scale, to give 16.8 g (92%) product as the free base. MS: exact mass calcd for C₁₅H₁₆BrNO, 305.0; m/z found, 306.1 [M+H]⁺, 308.1 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.24 (m, 2H), 7.03 (m, 3H), 6.64 (m, 3H), 4.66 (br s, 2H), 3.76 (m, 1H), 3.57 (s, 3H), 3.01 (m, 2H).

Step 7. N-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-succinamic acid. A solution of succinic anhydride (5.77 g, 57.6 mmol) in CH₂Cl₂ (55 mL) was stirred under nitrogen until homogeneous, cooled to 0° C., and then treated with a solution of 2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine (16.8 g, 54.9 mmol) in CH₂Cl₂ (55 mL). Once the addition was complete, the ice bath was removed and the mixture was stirred at rt for 2.5 h. The mixture was concentrated to give the crude product. The crude material was immediately taken on to the next step without purification. MS: exact mass calcd for C₁₉H₂₀BrNO₄, 405.1; m/z found, 406.0 [M+H]⁺, 408.0 [M+H]⁺.

Step 8. 1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione. A solution of the crude product from Step 7 (54.9 mmol) in EtOAc (55 mL) was treated with acetyl chloride (14.0 mL) and then was heated at reflux overnight. The mixture was cooled, and a precipitate formed. The solid was filtered to provide 15.9 g (75%) of the desired product. The filtrate was purified by chromatography (EtOAc/hexanes) to give an additional 3.28 g, for a combined yield of 19.2 g (90%). MS: exact mass calcd for C₁₉H₁₈BrNO₃, 387.1; m/z found, 410.0 [M+Na]⁺, 412.0 [M+Na]⁺. ¹H NMR (CDCl₃): 7.38 (m, 2H), 7.19 (m, 3H), 6.81 (d, J=7.6, 1H), 6.73 (m, 2H), 4.60 (t, J=8.4, 1H), 4.06 (m, 2H), 3.74 (s, 3H), 2.51 (s, 4H).

Step 9. 1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrrolidin-2-one. A mixture of 1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione (5.21 g, 13.4 mmol) in 1,4-dioxane (65 mL) was stirred until homogeneous and then was treated with ethanol (65 mL) and cooled to 0° C. Once cold, the mixture was treated with NaBH₄ (2.13 g, 56.4 mmol), followed by MSA (2 N in ethanol, 5 drops). Equivalent portions of MSA were added every 15 min over 5.5 h, after which time additional MSA was added to quench the NaBH₄ and to lower the pH to 1. The resulting viscous mixture was stirred for 3.5 h. The mixture was diluted with diethyl ether, washed with satd. aq. NaHCO₃, water, and brine, dried (MgSO₄), and concentrated to give the crude product.

Chromatographic purification (EtOAc/hexanes) yielded 4.30 g (76%) of the desired product. MS: exact mass calcd for C₂₁H₂₄BrNO₃, 417.1; m/z found, 440.0 [M+Na]⁺, 442.0 [M+Na]⁺. ¹H NMR (acetone-d₆): 7.46 (m, 2H), 7.32 (m, 2H), 7.23 (m, 1H), 6.90 (m, 2H), 6.76 (m, 1H), 4.63 (m, 1H), 4.42 (m, 1H), 4.15 (m, 1H), 3.75 (m, 3H), 3.61 (m, 1H), 3.41 (m, 2H), 2.29 (m, 1H), 2.04 (m, 1H), 1.84 (m, 2H), 1.13 (m, 3H).

Step 10. A mixture of 1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrrolidin-2-one (472.2 mg, 1.13 mmol) and MSA (2 N in ethanol, 10 mL) was stirred for 2 h at rt. The mixture was diluted with EtOAc, washed with satd. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated to give a colorless oil. Chromatographic purification (EtOAc/hexanes) yielded 325.4 mg (78%) of the desired product as a mixture of cis and trans diastereomers. The diastereomers were separated by normal-phase HPLC.

Trans-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. MS: exact mass calcd for C₁₉H₁₈BrNO₂, 371.1; m/z found, 372.0 [M+H]⁺, 374.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (m, 2H), 7.07 (m, 3H), 6.82 (m, 1H), 6.29 (d, J=1.9, 1H), 4.87 (m, 1H), 4.41 (m, 1H), 4.10 (m, 1H), 3.62 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.47 (m, 1H), 2.42 (m, 1H).

Cis-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. The cis isomer was processed as described in Example 43 below. MS: exact mass calcd for C₁₉H₁₈BrNO₂, 371.1; m/z found, 372.3 [M+H]⁺, 374.3 [M+H]⁺. ¹H NMR (acetone-d₆): 7.36 (m, 2H), 6.98 (m, 3H), 6.70 (d, J=8.0, 1H), 6.24 (d, J=7.5, 1H), 4.89 (m, 1H), 4.34 (dd, J=6.0, 12.8, 1H), 3.98 (dd, J=5.5, 11.2, 1H), 3.79 (s, 3H), 2.89 (m, 1H), 2.83 (m, 1H), 2.48 (m, 1H), 2.33 (m, 1H), 1.64 (m, 1H).

Step 11. Trans-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. A solution of the product from Step 10 (2.56 mmol, 1.0 equiv.) in CH₂Cl₂ (0.1 M) was treated with BBr₃ (1.0 M in CH₂Cl₂, 5 equiv.). The mixture was stirred overnight and then poured onto a mixture of crushed ice and CH₂Cl₂. The mixture was diluted with water and the layers were separated. The organic layer was washed with water (×2) and brine, dried (MgSO₄), and concentrated to give the crude product (776.0 mg) as a mixture of the desired product and the corresponding des-bromo material (trans-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one). The crude product was taken on to the next step without purification. Brominated product: MS (ESI, negative ionization): exact mass calcd for C₁₈H₁₆BrNO₂, 357.0; m/z found, 355.9 [M−H]⁻, 357.9 [M−H]⁻. Des-bromo product: MS: exact mass calcd for C₁₈H₁₇NO₂, 279.1; m/z found, 278.0 [M−H]⁻.

Step 12. Trans-6-(4-Bromo-phenyl)-8-(3-chloro-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. A mixture of the crude material from Step 11 (2.43 mmol, 1.0 equiv.), K₂CO₃(5 equiv.), and 1,3-bromochloropropane (5.12 mmol, 3 equiv.) in acetone (0.1 M) was heated at 60° C. overnight. The reaction mixture was diluted with CH₂Cl₂, filtered and concentrated. The crude product was purified by chromatography (EtOAc/hexanes) to provide a mixture of the desired product and trans-6-phenyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one (637.6 mg). Brominated product: MS: exact mass calcd for C₂₁H₂₁BrClNO₂, 433.0; m/z found, 434.0 [M+H]⁺, 436.0 [M+H]⁺. Des-bromo product: MS: exact mass calcd for C₂₁H₂₂ClNO₂, 355.1; m/z found, 356.1 [M+H]⁺.

Step 13. Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared from the product mixture from Step 12 (est. 1.61 mmol), as described in Example 39, Step 7. The reaction was performed in a glass pressure tube. Chromatographic purification (NH₃ in MeOH/CH₂Cl₂) gave a mixture of the desired product and trans-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one (683.9 mg). The product mixture was taken on to the next step without characterization.

Step 14. Prepared as described in Example 39, Step 8, on a 1.54 mmol scale (est.). Purification of the crude mixture of bromo and des-bromo compounds by reverse-phase HPLC gave the desired product (25.6 mg, 2%) as the TFA salt as well as 45.4 mg (4%) of the des-brominated product (Example 49). MS: exact mass calcd for C₂₆H₃₃N₂OBr, 468.2; m/z found, 469.1 [M+H]⁺, 471.1 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.51 (d, J=8.2, 2H), 7.29 (br d, J=7.8, 1H), 7.11 (br s, 2H), 6.98 (br d, J=6.9, 1H), 6.52 (br s, 1H), 4.57 (br s, 1H), 3.99 (m, 2H), 3.75 (br d, 2H), 3.53 (d, J=11.7, 2H), 4.45 (br m, 1H), 3.22 (t, J=7.8, 2H), 2.72 (br s, 1H), 2.15 (m, 5H), 1.91 (m, 2H), 1.79 (m, 3H), 1.50 (m, 1H).

Example 43

Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile

Step 1. Cis-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 11, on a 1.89 mmol scale, to yield 654.3 mg of a mixture of the desired product and cis-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one, the product of debromination under the reaction conditions. The crude product was taken on to the next step without purification or characterization.

Step 2. Cis-6-(4-Bromo-phenyl)-8-(3-chloro-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 12, on a 1.71 mmol scale, to yield 486.4 mg of a mixture of the desired product and cis-6-phenyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Brominated product: MS: exact mass calcd for C₂₁H₂₁BrClNO₂, 433.0; m/z found, 434.0 [M+H]⁺, 436.0 [M+H]⁺. Des-bromo product: MS: exact mass calcd for C₂₁H₂₂ClNO₂, 355.1; m/z found, 356.0 [M+H]⁺.

Step 3. Cis-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 13, on a 1.23 mmol scale to yield 308.1 mg of a mixture of the desired product and cis-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one.

Step 4. Prepared as described in Example 42, Step 14, on a 0.694 mmol scale. The crude product was divided into two equal portions. One portion was carried forward to prepare the nitrile and the other portion was subjected to reverse-phase HPLC to yield pure des-bromo product (Example 50). The bromo-product was not isolated as a pure substance.

Step 5. Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile. To a high-pressure reaction vial was added the product of Step 4 (1.06 mmol), CuCN (1.2 equiv.), and DMF (2.0 M). The sealed vial was heated at 150° C. for 2 d. The mixture was cooled to rt, diluted with aqueous NaCN, and extracted with diethyl ether. The combined organic extracts were combined, washed with water, satd. aq. NaHCO₃, and brine, dried (Na₂CO₃) and concentrated to give the crude product. The product was purified by reverse-phase HPLC to give 4.7 mg (0.7%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₇H₃₃N₃O, 415.3; m/z found, 416.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 4.72 (d, J=8.4, 2H), 7.31 (m, 3H), 7.03 (d, J=8.3, 1H), 6.59 (d, J=7.7, 1H), 5.02 (br m, 1H), 4.69 (m, 1H), 4.24 (m, 1H), 4.18 (m, 1H), 3.66 (m, 6H), 3.33 (m, 1H), 3.00 (m, 2H), 2.90 (br s, 1H), 2.32 (m, 2H), 2.19 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H), 1.55 (m, 1H).

Example 44

Trans-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Product was isolated by HPLC from the reaction described in Example 42, Step 14 (1.54 mmol scale), to yield 45.4 mg (4%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₆H₃₄N₂O, 390.3; m/z found, 391.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.37 (m, 2H), 7.32 (m, 2H), 7.18 (br s, 1H), 6.98 (br s, 1H), 6.53 (br s, 1H), 4.56 (br s, 1H), 3.98 (br m, 2H), 3.77 (br s, 1H), 3.66 (br s, 1H), 3.53 (d, J=11.7, 2H), 3.48 (br s, 1H), 3.22 (m, 2H), 2.90 (t, J=12.2, 2H), 2.74 (br s, 1H), 2.15 (br m, 5H), 1.90 (d, J=14.0, 2H), 1.77 (m, 3H), 1.48 (m, 1H).

Example 45

Cis-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Prepared as described in Example 42, Step 14, 0.694 mmol scale, to yield 15.3 mg (3%) of the desired product as the TFA salt. ¹H NMR (MeOH-d₄): 7.34 (m, 5H), 7.14 (d, J=7.2, 2H), 7.02 (d, J=8.2, 1H), 6.62 (d, J=7.7, 1H), 5.08 (m, 1H), 4.57 (m, 1H), 4.22 (m, 2H), 3.74 (m, 1H), 3.64 (m, 3H), 3.54 (m, 1H), 3.30 (m, 3H), 3.01 (m, 2H), 2.90 (m, 1H), 2.34 (m, 2H), 2.20 (m, 2H), 2.05 (m, 3H), 1.85 (m, 3H), 1.56 (m, 1H), 1.04 (m, 1H).

Example 46

Cis-6-(4-Methoxy-phenyl)-9-[3-(3S-methyl-morpholin-4-yl)-propoxy]-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Prepared as described in Example 38, Step 8, using (3S)-methylmorpholine, to give 62.0 mg (12%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₇H₃₆N₂O₃, 436.3; m/z found, 437.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.15 (d, J=8.5, 2H), 6.94 (d, J=8.5, 2H), 6.87 (br d, J=2.0, 1H), 6.80 (dd, J=2.0, 8.8, 1H), 6.72 (d, J=8.5, 1H), 4.84 (m, 1H), 4.33 (dd, J=4.5, 12.0, 1H), 4.11 (t, J=5.5, 2H), 4.00 (m, 2H), 3.85 (m, 2H), 3.79 (s, 3H), 3.56 (m, 4H), 3.31 (m, 6H), 2.82 (m, 1H), 2.27 (m, 5H), 1.33 (d, J=6.5, 3H).

Example 47

Cis-9-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Prepared as described in Example 38, Step 8, using 4-fluoropiperidine, to give 77.7 mg (14%) of the desired product as the TFA salt. MS: exact mass calcd for C₂₇H₃₅FN₂O₂, 438.3; m/z found, 439.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.15 (d, J=8.5, 2H), 6.94 (d, J=9.0, 2H), 6.87 (d, J=2.5, 1H), 6.79 (dd, J=2.0, 8.8, 1H), 6.72 (d, J=9.0, 1H), 4.98 (m, 1H), 4.84 (m, 1H), 4.34 (dd, J=4.5, 12.0, 1H), 4.09 (t, J=6.0, 2H), 3.86 (m, 1H), 3.79 (s, 3H), 3.68 (m, 1H), 3.56 (m, 2H), 3.32 (m, 6H), 2.82 (m, 1H), 2.24 (m, 8H).

Example 48(A-B)

48A: Cis-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

48B: Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Imidazol-1-yl-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.77 g (>100%) of crude product. MS: exact mass calcd for C₂₈H₃₄N₄O₃, 474.3; m/z found, 475.5 [M+H]⁺.

Step 2. 6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.43 mmol scale, to give 1.60 g (95%) of crude product. MS: exact mass calcd for C₂₈H₃₁N₄O₂ ⁺, 455.2; m/z found, 455.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.43 mmol scale, to give 579 mg (37%) of 48A and 63 mg (4%) of 48B after column chromatography and HPLC.

48A: Cis-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS: exact mass calcd for C₂₆H₃₃N₄O₂, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 9.52 (s, 1H), 8.10 (s, 1H), 7.79 (m, 3H), 7.57 (d, J=8.4, 2H), 6.93 (d, J=2.4, 1H), 6.82 (dd, J=1.8, 8.4, 1H), 6.71 (d, J=8.4, 1H), 4.92 (t, J=7.2, 1H), 4.61 (dd, J=4.2, 12.0, 1H), 4.12 (t, J=6.0, 2H), 4.05 (d, J=12.0, 2H), 3.92 (m, 1H), 3.82 (t, J=12.0, 2H), 3.69 (dd, J=4.8, 11.7, 1H), 3.57 (d, J=12.6, 2H), 3.51 (t, J=12.0, 1H), 3.45 (m, 1H), 3.39 (t, J=7.8, 2H),3.18 (m, 2H), 2.87 (m, 1H), 2.30 (br m, 5H).

48B: Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS: exact mass calcd for C₂₆H₃₃N₄O₂, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 9.47 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.73 (d, J=6.0, 2H), 7.44 (br s, 2H), 6.93 (m, 3H), 4.71 (br s, 1H), 4.15 (t, J=5.4, 2H), 4.07 (d, J=12.0, 2H), 3.82 (m, 4H), 3.58 (d, J=11.4, 2H), 3.40 (t, J=7.8, 2H), 3.21 (br m, 2H), 2.82 (br s, 1H), 2.29 (m, 2H), 2.19 (br s, 2H).

Example 49

Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-pyrazol-1-yl-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.91 g (>100%) of crude product. MS: exact mass calcd for C₂₈H₃₄N₄O₃, 474.3; m/z found, 475.5 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.56 g (92%) of crude product. MS: exact mass calcd for C₂₈H₃₁N₄O₂ ⁺, 455.2; m/z found, 455.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.17 mmol scale, to give 135 mg (9%) of the desired product after column chromatography and recrystallization from hot IPA. ¹H NMR (CDCl₃): 7.86 (d, J=2.0, 1H), 7.69 (d, J=1.6, 1H), 7.56 (d, J=6.8, 2H), 7.30 (d, J=8.4, 2H), 6.81 (d, J=8.4, 1H), 6.69 (d, J=2.4, 1H), 6.65 (dd, J=2.8, 8.4, 1H), 6.42 (m, 1H), 4.15 (t, J=4.8, 1H), 3.99 (t, J=6.4, 2H), 3.72 (m, 4H), 3.46 (m, 1H), 3.02 (dd, J=4.8, 11.2, 1H), 2.96 (m, 1H), 2.86 (dd, J=4.8, 11.0, 1H), 2.61-2.46 (br m, 8H), 2.34 (m, 1H), 1.95 (m, 3H), 1.82 (m, 2H).

Example 50(A-B)

50A: Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

50B: Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyrazin-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.43 mmol scale, to give 1.40 g (>100%) of crude product. MS: exact mass calcd for C₂₃H₃₀N₄O₃, 410.2; m/z found, 411.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.43 mmol scale, to give the crude product. MS: exact mass calcd for C₂₃H₂₇N₄O₂ ⁺, 391.2; m/z found, 391.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.17 mmol scale, to give 155 mg (11%) of product A and 23 mg (2%) of product B after column chromatography and HPLC.

50A: Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS: exact mass calcd for C₂₃H₃₀N₄O₂, 394.2; m/z found, 395.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.48 (d, J=1.8, 1H), 8.37 (d, J=2.4, 1H), 8.32 (d, J=0.6, 1H), 6.77 (d, J=8.4, 1H), 6.73 (d, J=2.4, 1H), 6.67 (dd, J=2.4, 8.4, 1H), 4.31 (t, J=4.2, 1H), 3.97 (m, 2H), 3.65 (m, 4H), 3.37 (dd, J=7.2, 9.9, 1H), 3.21 (dd, J=4.2, 11.4, 1H), 2.89 (m, 2H), 2.49 (t, J=7.8, 2H), 2.43 (br s, 4H), 2.34 (m, 1H), 1.91 (m, 3H), 1.83-1.73 (m, 2H).

50B: Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS: exact mass calcd for C₂₃H₃₀N₄O₂, 394.2; m/z found, 395.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.53 (d, J=1.2, 1H), 8.36 (d, J=2.4, 1H), 7.97 (d, J=1.2, 1H), 7.25 (m, 1H), 6.84 (d, J=7.8, 1H), 6.78 (d, J=8.4, 1H), 4.40 (d, J=4.2, 1H), 4.03 (t, J=6.0, 1H), 3.91 (m, 1H), 3.70 (m, 2H), 3.62 (m, 4H), 3.29 (m, 1H), 3.25 (m, 1H), 2.84 (m, 2H), 2.53 (m, 1H), 2.47 (br s, 1H), 2.40 (m, 1H), 2.30 (m, 5H), 1.96 (m, 3H), 1.84 (m, 2H), 1.73 (m, 1H), 1.61 (m, 1H), 1.56 (m, 1H).

Example 51(A-B)

51A: Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol

51B: Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol

Step 1. 1-(6-Hydroxy-pyridin-3-yl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 590 mg (40%) of product after column chromatography. MS: exact mass calcd for C₂₄H₃₁N₃O₄, 425.2; m/z found, 426.5 [M+H]⁺. ¹H NMR (acetone-d₆): 8.37 (d, J=2.4, 1H), 7.82 (dd, J=3.0, 9.6, 1H), 7.22 (t, J=7.8, 1H), 6.96 (m, 2H), 6.79 (m, 1H), 6.34 (d, J=10.2, 1H), 4.03 (m, 2H), 3.78 (d, J=14.4, 1H), 3.60 (m, 4H), 3.41 (t, J=8.4, 1H), 3.27 (m, 1H), 3.25 (d, J=14.4, 1H), 2.47 (t, J=6.6, 2H), 2.38 (m, 5H), 2.19 (m, 1H), 1.92 (m, 3H), 1.84 (m, 1H), 1.73 (m, 1H).

Step 2. 6-(6-Hydroxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 1.32 mmol scale, to give 230 mg (40%) of crude product. MS: exact mass calcd for C₂₄H₂₈N₃O₃ ⁺, 406.2; m/z found, 406.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 0.453 mmol scale, to give 71.9 mg (25%) of 50A and 71.3 mg (25%) of 50B after column chromatography and HPLC.

51A: Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol. MS: exact mass calcd for C₂₄ H₃₁N₃O₃, 409.2; m/z found, 410.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.37 (s, 1H), 7.21 (d, J=8.4, 1H), 6.68 (m, 3H), 6.40 (d, J=9.6, 1H), 4.67 (m, 1H), 4.11 (dd, J=4.2, 12.0, 1H), 3.91 (t, J=5.4, 2H), 3.86 (br d, J=12.6, 2H), 3.67 (m, 1H), 3.60 (t, J=12.0, 2H), 3.37 (m, 3H), 3.22 (m, 1H), 3.18 (m, 2H), 2.97 (m, 2H), 2.06 (m, 5H),

51B: Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol. MS: exact mass calcd for C₂₄ H_(3i)N₃O₃, 409.2; m/z found, 410.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.32 (br s, 1H), 6.84 (br s, 1H), 6.72 (m, 2H), 6.37 (d, J=9.6, 1H), 4.69 (br s, 1H), 4.18 (br s, 1H), 3.92 (t, J=5.4, 2H), 3.85 (d, J=12.6, 2H), 3.76 (s, 1H), 3.59 (t, J=12.0, 3H), 3.35 (d, J=12.0, 2H), 3.17 (m, 3H), 2.96 (br t, J=11.4, 2H), 2.55 (br s, 1H), 2.05 (m, 2H), 1.94 (br s, 3H).

Example 52

Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiazol-5-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.18 g (81%) of product after column chromatography. MS: exact mass calcd for C₂₂H₂₉N₃O₃S, 415.2; m/z found, 416.4 [M+H]⁺. ¹H NMR (acetone-d₆): 9.21 (s, 1H), 8.57 (s, 1H), 7.22 (t, J=7.8, 1H), 7.03 (m, 1H), 6.98 (d, J=7.8, 1H), 6.81 (m, 1H), 5.62 (s, 1H), 4.02 (m, 3H), 3.89 (d, J=16.2, 1H), 3.60 (m, 5H), 3.52 (t, J=8.4, 1H), 3.38 (d, J=15.6, 1H), 3.30 (m, 1H), 2.45 (m, 9H), 2.22 (m, 1H), 1.90 (m, 5H), 1.78 (m, 1H).

Step 2. 9(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 2.77 mmol scale, to give 680 mg (57%) of crude product. MS: exact mass calcd for C₂₂H₂₆N₃O₂S⁺, 396.2; m/z found, 396.4 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.57 mmol scale, to give 538 mg (86%) of product after column chromatography. MS: exact mass calcd for C₂₂H₂₉N₃O₂S, 399.2; m/z found, 400.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.63 (s, 1H), 7.72 (s, 1H), 6.90 (s, 1H), 6.62 (m, 2H), 4.39 (s, 1H), 3.90 (m, 2H), 3.61 (m, 4H), 3.24 (m, 1 H), 2.97 (m, 2H), 2.75 (dd, J=4.2, 11.4, 1 H), 2.38 (m, 7H), 2.30 (m, 1H), 1.80 (m, 4H), 1.66 (m, 1H).

Example 53

Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiazol-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 680 mg (46%) of product after column chromatography. MS: exact mass calcd for C₂₂H₂₉N₃O₃S, 415.2; m/z found, 416.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 1.64 mmol scale, to give 1.00 g (>100%) of crude product. MS: exact mass calcd for C₂₂H₂₆N₃O₂S⁺, 396.2; m/z found, 396.4 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.64 mmol scale, to give 237 mg (38%) of product after column chromatography. MS: exact mass calcd for C₂₂H₂₉N₃O₂S, 399.2; m/z found, 400.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.58 (d, J=3.6, 1H), 7.29 (d, J=3.6, 1H), 7.00 (m, 1H), 6.66 (m, 2H), 4.46 (m, 1H), 3.93 (m, 2H), 3.63 (m, 4H), 3.26 (m, 2H), 2.99 (m, 1H), 2.83 (dd, J=4.2, 11.4, 1H), 2.43 (m, 7H), 2.33 (m, 1H), 1.90 (m, 3H), 1.80 (m, 1H), 1.69 (m, 1H),

Example 54

Cis-9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(2H-pyrazol-3-yl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 940 mg (65%) of product after filtration and evaporation to dryness. MS: exact mass calcd for C₂₂H₃₀N₄O₃, 398.2; m/z found, 399.5 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 2.36 mmol scale, to give the crude product. MS: exact mass calcd for C₂₂H₂₇N₄O₂ ⁺, 379.2; m/z found, 379.5 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.36 mmol scale, to give 467 mg (52%) of product after column chromatography. MS: exact mass calcd for C₂₂H₃₀N₄O₂, 382.2; m/z found, 383.5 [M+H]⁺. ¹H NMR (acetone-d₆): 11.56 (br s, 1H), 7.35 (s, 1H), 7.00 (m, 1H), 6.68 (m, 2H), 6.06 (s, 1H), 4.22 (br s, 1H), 4.01 (m, 2H), 3.59 (m, 4H), 3.22 (m, 2H), 3.10 (br m, 1H), 2.76 (dd, J=4.2, 11.1, 1H), 2.45 (t, J=7.2, 2H), 2.37 (m, 6H), 1.98 (m, 1H), 1.90 (t, J=7.2, 2H), 1.88 (m, 1H), 1.75 (m, 1H).

Example 55

Cis-6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-Imidazo[1,2-a]pyridin-3-yl-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.38 g (85%) of product after chromatography. MS: exact mass calcd for C₂₆H₃₂N₄O₃, 448.2; m/z found, 449.5 [M+H]⁺. ¹H NMR (acetone-d₆): 9.55 (d, J=7.0, 1H), 8.44 (s, 1H), 7.73 (d, J=9.0, 1H), 7.60 (m, 1H), 7.21 (m, 2H), 7.02 (d, J=1.5, 1H), 6.97 (d, J=7.5, 1H), 6.77 (dd, J=2.0, 8.2, 1H), 5.62 (s, 1H), 3.99 (m, 2H), 3.92 (d, J=15.0, 1H), 3.58 (m, 4H), 3.52 (t, J=8.5, 1H), 3.38 (m, 1H), 3.37 (d, J=14.5, 1H), 2.49 (m, 1H), 2.45 (t, J=7.0, 2H), 2.38 (br s, 4H), 2.20 (m, 1H), 1.89 (m, 4H), 1.75 (m, 1H).

Step 2. 6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 2.94 mmol scale, to give 1.74 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₂₉N₄O₂ ⁺, 429.2; m/z found, 429.3 [M]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.94 mmol scale, to give 652 mg (51%) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₅N₄O₂, 432.2; m/z found, 433.3 [M+H]⁺. ¹H NMR (acetone-d₆): 8.57 (m, 1H), 7.48 (m, 1H), 7.23 (s, 1H), 7.12 (m, 1H), 6.87 (d, J=9.0, 1H), 6.70 (m, 3H), 4.67 (m, 1H), 4.02 (m, 2H), 3.59 (m, 4H), 3.26 (m, 2H), 2.97 (m, 1H), 2.87 (m, 2H), 2.46 (t, J=6.6, 2H), 2.37 (m, 6H), 1.85 (m, 6H).

Example 56

Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiophen-3-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.58 g (>100%) of the crude product. MS: exact mass calcd for C₂₃H₃₀N₂O₃S, 414.2; m/z found, 415.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.34 g (99%) of the crude product. MS: exact mass calcd for C₂₃H₃₀N₂O₃S⁺, 395.2; m/z found, 395.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.39 mmol scale, to give 612 mg (38%) of product after column chromatography. MS: exact mass calcd for C₂₃H₃₀N₂O₂S, 398.2; m/z found, 399.4 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄): 7.47 (m, 1H), 7.39 (m, 1H), 6.94 (m, 1H), 6.91 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.11 (m, 2H), 4.05 (m, 2H), 3.83 (m, 3H), 3.57 (m, 3H), 3.49 (m, 1H), 3.37 (m, 4H), 3.18 (m, 2H), 2.84 (m, 1H), 2.26 (m, 5H).

Example 57

Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thiophen-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.83 g (>100%%) of the crude product. MS: exact mass calcd for C₂₃H₃₀N₂O₃S, 414.2; m/z found, 415.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.50 g (>100%) of the crude product. MS: exact mass calcd for C₂₃H₃₀N₂O₃S⁺, 395.2; m/z found, 395.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.44 mmol scale, to give 370 mg (17% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₃H₃₀N₂ 0 ₂S, 398.2; m/z found, 399.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.50 (m, 1H), 7.16 (m, 1H), 7.11 (m, 1H), 6.93 (d, J=2.5, 1H), 6.87 (d, J=8.7, 1H), 6.82 (dd, J=2.5, 8.7, 1H), 4.93 (m, 2H), 4.13 (t, J=6.0, 2H), 3.96 (m, 5H), 3.78 (dd, J=4.6, 12.0, 1H), 3.61 (d, J=12.2, 2H), 3.44 (m, 4H), 3.19 (m, 2H), 2.89 (m, 1H), 2.30 (m, 5H).

Example 58

Cis-3-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile

Step 1. 3-(2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-acetyl)-benzonitrile. Prepared as described in Example 8, Step 1, on a 1.72 mmol scale, to give 0.86 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₁ N₃O₃, 433.2; m/z found, 434.5 [M+H]⁺.

Step 2. 6-(3-Cyano-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 1.72 mmol scale, to give 0.81 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₂₈N₃O₂ ⁺, 414.2; m/z found, 414.5 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 1.72 mmol scale, to give 70 mg (6% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₁N₃O₂, 417.2; m/z found, 418.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.77 (m, 1H), 7.67 (m, 3H), 6.96 (m, 1H), 6.79 (dd, J=2.5, 8.7, 1H) 6.62 (d, J=8.6, 1H), 4.93 (m, 1H), 4.73 (m, 1H), 4.13 (t, J=6.0, 2H), 3.94 (m, 5H), 3.72 (m, 1H), 3.59 (m, 3H), 3.40 (m, 3H), 3.14 (m, 2H), 2.89 (m, 1H), 2.33 (m, 5H).

Example 59

Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyridin-3-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.52 g (>100%) of the crude product. MS: exact mass calcd for C₂₄ H₃₁N₃O₃, 409.2; m/z found, 410.5 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.00 g (75%) of the crude product. MS: exact mass calcd for C₂₄H₂₈N₃O₂ ⁺, 390.2; m/z found, 390.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 2.56 mmol scale, to give 285 mg (18%) of product after column chromatography. MS: exact mass calcd for C₂₄H₃₁N₃O₂, 393.2; m/z found, 394.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 8.50 (m, 1H), 8.34 (dd, J=1.6, 4.7, 1H), 7.59 (m, 1H), 7.17 (m, 1H), 6.81 (d, J=8.5, 1H), 6.72 (m, 1H), 6.67 (dd, J=2.6, 8.5, 1H), 4.13 (m, 1H), 4.01 (m, 2H), 3.58 (m, 4H), 3.15 (m, 1H), 3.07 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.38 (m, 8H), 1.88 (m, 4H), 1.74 (m, 1H).

Example 60

Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyridin-2-yl-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.61 g (>100%) of the crude product. MS: exact mass calcd for C₂₄H₃₁N₃O₃, 409.2; m/z found, 410.5 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.34 g (>100%) of the crude product. MS: exact mass calcd for C₂₄H₂₈N₃O₂ ⁺, 390.2; m/z found, 390.5 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.44 mmol scale, to give 200 mg (13% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₄H₃₁N₃O₂, 393.2; m/z found, 394.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 8.47 (m, 1H), 7.53 (m, 1H), 7.10 (m, 2H), 6.88 (d, J=11.3, 1H), 6.70 (m, 2H), 4.22 (m, 1H), 4.02 (m, 2H), 3.58 (m, 4H), 3.28 (dd, J=2.2 11.2, 1H), 3.16 (m, 1H), 2.91 (m, 1H), 2.79 (m, 1H), 2.39 (m, 8H), 1.85 (m, 4H), 1.69 (m, 1H).

Example 61

Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-trifluoromethylsulfanyl-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 2.10 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₂₈F₃N₂O₃S, 508.2; m/z found, 509.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.34 mmol scale, to give 2.30 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₂₈F₃N₂O₂S⁺, 489.2; m/z found, 489.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.34 mmol scale, to give 568 mg (24% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₁F₃N₂O₂S, 492.2; m/z found, 493.4 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.75 (d, J=8.1, 2H), 7.47 (d, J=8.1, 2H), 6.96 (m, 1H), 6.80 (dd, J=2.5, 8.6, 1H), 6.61 (d, J=10.9, 1H), 4.93 (m, 1H), 4.69 (dd, J=4.6, 12.0, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 5H), 3.72 (m, 1H), 3.61 (m, 2H), 3.51 (m, 1H), 3.41 (m, 3H), 3.18 (m, 2H), 2.88 (m, 1H), 2.30 (m, 5H).

Example 62

Cis-9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3-trifluoromethylsulfanyl-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 2.00 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₁F₃N₂O₃S, 508.2; m/z found, 509.4 [M+H]⁺.

Step 2. 9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.80 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₂₈F₃N₂O₂S⁺, 489.2; m/z found, 489.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.44 mmol scale, to give 247 mg (10% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₁F₃N₂O₂S, 492.2; m/z found, 493.5 [M+H]⁺. (500 MHz, acetone-d₆): 7.83 (d, J=16.7, 1H), 7.66 (s, 1H), 7.58 (m, 2H), 6.97 (m, 1H), 6.79 (dd, J=2.6, 8.7, 1H), 6.62 (d, J=8.6, 1H), 4.92 (m, 1H), 4.70 (m, 1H), 4.14 (m, 2H), 3.95 (m, 5H), 3.74 (m, 1H), 3.59 (m, 3H), 3.41 (m, 3H), 3.17 (m, 2H), 2.90 (m, 1H), 2.31 (m, 5H).

Example 63

Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Methylsulfanyl-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.95 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₄N₂O₃S, 454.2; m/z found, 455.5 [M+H]⁺.

Step 2. 6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.45 g (97%) of the crude product. MS: exact mass calcd for C₂₆H₃₁N₂O₂S⁺, 435.2; m/z found, 435.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.33 mmol scale, to give 82 mg (4%) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₄N₂O₂S, 438.2; m/z found, 439.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.29 (d, J=8.4, 2H), 7.21 (d, J=8.3, 2H), 6.94 (m, 1H), 6.78 (m, 1H), 6.66 (d, J=8.7, 1H), 4.92 (m, 1H), 4.53 (m, 1H), 4.13 (t, J=6.0, 2H), 3.94 (m, 5H), 3.63 (m, 3H), 3.43 (m, 4H), 3.16 (m, 2H), 2.89 (m, 1H), 2.49 (s, 3H), 2.30 (m, 5H).

Example 64

Cis-6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Chloro-4-methoxy-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.92 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₃ClN₂O₄, 472.2; m/z found, 473.5 [M+H]⁺.

Step 2. 6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.85 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₀ClN₂O₃ ⁺, 453.2; m/z found, 453.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.44 mmol scale, to give 340 mg (14% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₃ClN₂O₃, 456.2; m/z found, 457.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.26 (m, 2H), 7.14 (d, J=8.4, 1H), 6.94 (m, 1H), 6.79 (dd, J=2.5, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.91 (m, 1H), 4.53 (dd, J=4.6, 12.1, 1H), 4.13 (t, J=6.0, 2H), 3.99 (m, 2H), 3.90 (m, 7H), 3.64 (m, 3H), 3.50 (m, 1H), 3.40 (m, 3H), 3.17 (m, 2H), 2.88 (m, 1H), 2.34 (m, 5H), 2.25 (m, 1H).

Example 65

Cis-6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(3-Chloro-4-fluoro-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.44 mmol scale, to give 1.80 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₃FN₂O₄, 456.2; m/z found, 457.5 [M+H]⁺.

Step 2. 6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium. Prepared as described in Example 17, Step 2, on a 3.44 mmol scale, to give 1.50 g (>100%) of the crude product. MS: exact mass calcd for C₂₆H₃₀FN₂O₃ ⁺, 437.2; m/z found, 437.4 [M+H]⁺.

Step 3. Prepared as described in Example 17, Step 3, on a 3.44 mmol scale, to give 415 mg (18% over 3 steps) of product after column chromatography. MS: exact mass calcd for C₂₆H₃₃FN₂O₃, 440.3; m/z found, 441.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.15 (m, 1H), 7.09 (m, 1H), 7.02 (dd, J=1.9, 12.4, 1H), 6.93 (m, 1H), 6.79 (dd, J=2.5, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.90 (m, 1H), 4.52 (dd, J=4.5, 12.0, 1H), 4.13 (t, J=6.0, 2H), 3.93 (m, 8H), 3.63 (m, 3H), 3.44 (m, 1H), 3.39 (m, 3H), 3.15 (m, 2H), 2.88 (m, 1H), 2.33 (m, 5H).

Example 66-(A-B)

66A: Cis-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

66B: Trans-6-(4-chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-(4-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale to give 1.70 g (>100%) of the desired product as a mixture of diastereomers. MS: exact mass calcd for C₂₆H₃₅ClN₂O₂, 476.3; m/z found, 477.4 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 3.19 mmol scale, to give the desired products 66A and 66B, which were separated by HPLC.

66A: 6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 8.0 mg (0.4%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.4 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.44 (d, J=8.4, 2H), 7.33 (d, J=8.3, 2H), 6.96 (s, 1H), 6.80 (d, 8.7, 1H), 6.66 (d, J=8.7, 1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.13 (m, 2H), 3.95 (m, 1H), 3.65 (m, 3H), 3.46 (m, 1H), 3.40 (m, 1H), 3.33 (m, 2H), 2.91 (m, 3H), 2.34 (m, 5H), 1.90 (m, 4H), 1.81 (m, 1H), 1.52 (m, 1H).

66B: 6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 205 mg (9%) as the TFA salt. MS: exact mass calcd for C₂₆H₃₃ClN₂O, 424.2; m/z found, 425.4 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.40 (d, J=8.8, 2H), 7.29 (d, J=8.4, 2H), 6.99 (br s, 1H), 6.86 (dd, J=2.5, 8.6, 1H), 6.82 (d, J=8.7, 1H), 5.14 (br s, 1H), 4.64 (br s, 1H), 4.17 (m, 2H), 3.81 (br s, 1H), 3.65 (m, 4H), 3.53 (br s, 1H), 3.34 (m, 2H), 2.99 (m, 2H), 2.77 (br s, 1H), 2.35-2.32 (m, 2H), 2.20 (m, 2H), 2.10 (m, 1H), 1.92 (m, 4H), 1.80 (m, 1H), 1.54 (m, 1H).

Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trifluoromethyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanol. Prepared as described in Example 1, Step 6, on a 3.47 mmol scale to give 1.52 g (92%) of product. MS: exact mass calcd for C₂₇H₃₅F₃N₂O₂, 476.3; m/z found, 477.4 [M+H]⁺.

Step 2. Performed as described in Example 1, Step 7, on a 3.19 mmol scale to give 36.0 mg (2%) of product after chromatography. MS: exact mass calcd for C₂₇H₃₃F₃N₂O, 458.3; m/z found, 459.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆); 7.90 (m, 1H), 7.82 (m, 3H), 7.13 (s, 1H), 6.95 (d, J=8.6, 1H), 6.78 (d, 8.7, 1H), 5.09 (m, 1H), 4.91 (m, 1H), 4.28 (t, J=5.8, 2H), 3.90 (m, 1H), 3.88 (m, 1H), 3.76 (m, 3H), 3.57 (m, 1H), 3.48 (m, 2H), 3.14 (m, 2H), 3.05 (m, 1H), 2.46 (m, 4H), 2.21 (m, 1H), 2.05 (m, 4H), 1.95 (m, 1H), 1.66 (m, 1H).

The following compounds in Examples 68-87 may be prepared according to the methods described above.

Example 68

6-Biphenyl-4-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 69

9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 70

9-(3-Morpholin-4-yl-propoxy)-6-quinolin-7-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 71

6-(1H-Indol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 72

6-(1H-Benzoimidazol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 73

6-(1H-Benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 74

6-(1-Methyl-1H-benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 75

9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-1-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 76

6-Benzo[b]thiophen-7-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 77

6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 78

Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine Example 79

6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 80

9-(3-Morpholin-4-yl-propoxy)-6-oxazol-5-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 81

6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 82

6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 83

6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 84

6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 85

6-(3-Chloro-4-difluoromethoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 86

(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl}-morpholin-2-yl)-methanol Example 87

(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl}-morpholin-3-yl)-methanol Example 88

6-(3,5-Bis-trifluoromethyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline Example 89

(1R,6S)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Separation of the enantiomers from racemic cis-6-(4-methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline gave the title compound and Example 90. MS: exact mass calcd for C₂₆H₃₄N₂O₂S, 438.23; m/z found, 439.2 [M+H]⁺.

Example 90

(1S,6R)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

MS: exact mass calcd for C₂₆H₃₄N₂O₂S, 438.23; m/z found, 439.2 [M+H]⁺.

Example 91

(1S,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Separation of the enantiomers from racemic cis-6-(4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline gave the title compound and Example 92. MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.26; m/z found, 423.5 [M+H]⁺.

Example 92

(1R,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.26; m/z found, 423.5 [M+H]⁺.

Example 93

Trans-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

The title compound was prepared as described in the preceding examples. The racemic material was separated by chiral HPLC to provide Examples 94 and 95.

MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.26; m/z found, 423.5 [M+H]⁺.

Example 94

(1R,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.26; m/z found, 423.5 [M+H]⁺.

Example 95

(1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

MS: exact mass calcd for C₂₆H₃₄N₂O₃, 422.26; m/z found, 423.5 [M+H]⁺.

Example 96-(A-B)

96A: Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

96B: Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 5-(3-Bromo-phenyl)-3,4-dihydro-2H-pyrrole. Prepared as described in Example 1, Step 4, on a 0.19 mol scale, using 3 N HCl in place of 12 N HCl during the workup procedure, to give 47.4 g of the desired product. MS (ESI): exact mass calcd for C₁₀H₁₀BrN, 223.0; m/z found, 224.0 [M+H]⁺, 226.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.00 (m, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.41 (m, 1H), 3.97 (t, J=6.9 Hz, 2H), 2.91 (t, J=7.7 Hz, 2H), 1.93 (m, 2H).

Step 2. 2-(3-Bromo-phenyl)-pyrrolidine. A solution of 5-(3-bromo-phenyl)-3,4-dihydro-2H-pyrrole (0.21 mol) in absolute ethanol (1.2 M) was treated portionwise with NaBH₄ (1.0 equiv.). The resultant mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and slowly quenched with 1 N HCl. The mixture was acidified to a pH of 1 with 3 N HCl and was stirred at room temperature for 45 min. The resulting mixture was again cooled to 0° C., and was treated with 1 N NaOH until basic. The aqueous mixture was extracted with CH₂Cl₂ (×3). The combined extracts were washed with brine, dried (MgSO₄), filtered and concentrated to give the crude product. Chromatography (EtOAc/hexanes) gave 39.8 g (84%) of the desired product. MS (ESI): exact mass calcd for C₁₀H₁₂BrN, 225.1; m/z found, 226.0 [M+H]⁺, 228.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.74 (m, 1H), 7.57 (m, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 4.37 (m, 1H), 3.24 (m, 1H), 3.16 (m, 1H), 2.32 (m, 1H), 2.00 (m, 1H), 1.94 (m, 1H), 1.81 (m, 1H).

Step 3. 2-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-1-(4-methoxy-phenyl)-ethanone. To a solution of 2-(3-bromo-phenyl)-pyrrolidine (3.8 g, 16.8 mmol) and Hunig's base (5.9 mL, 33.6 mmol) in THF (170 mL) was added 2-bromo-1-(4-methoxy-phenyl)-ethanone (4.6 g, 20.2 mmol). The mixture was stirred at room temperature for 5 h, concentrated, and purified by normal phase column chromatography (NH₃ in MeOH/CH₂Cl₂) to give 4.75 g (75%) of the product as a yellow oil. MS (ESI): exact mass calcd for C₁₉H₂₀BrNO₂, 373.1; m/z found, 374.3 [M+H]⁺, 376.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.84 (d, J=9.0 Hz, 2H), 7.58 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 6.87 (d, J=9.0 Hz, 2H), 3.99 (d, J=15.6 Hz, 1H), 3.85 (s, 3H), 3.50 (t, J=8.1 Hz, 1H), 3.39 (m, 1H), 2.42 (m, 1H), 2.21 (m, 1H), 1.97 (m, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.61 (s, 1H).

Step 4. 2-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-1-(4-methoxy-phenyl)-ethanol. Prepared as described in Example 8, Step 2, on a 6.68 mmol scale, to give 2.26 g (90%) of the crude product as a mixture of diastereomers. MS (ESI): exact mass calcd for C₁₉H₂₂BrNO₂, 375.1; m/z found, 376.3 [M+H]⁺, 378.3 [M+H]⁺.

Step 5. 9-Bromo-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline and 7-Bromo-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. Prepared as described in Example 1, Step 7, to give a 48% combined yield (over 2 steps) of the two regioisomers, each as a set of two diastereomers. MS (ESI): exact mass calcd for C₁₉H₂₀BrNO, 357.1, m/z found, 358.3 [M+H]⁺, 360.3 [M+H]⁺.

Step 6. Performed on the mixture of isomers from Step 5 as described in Example 33, on a 1.73 mmol scale, using 1-but-3-ynylpiperidine, to give a 20% combined yield of two diastereomers. After HPLC purification, the products were converted from their TFA salts to their corresponding HCl salts by azeotrope (3×) with HCl in dioxane.

96A: Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 15.0 mg (2%) as the HCl salt. MS (ESI): exact mass calcd for C₂₆H₃₄N₂O, 414.3; m/z found, 415.5 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.45 (br s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 6.80 (d, J=7.9 Hz, 1H), 4.46 (d, 1H), 3.90 (m, 1H, 3.81 (s, 3H), 3.76 (m, 1H), 3.44 (m, 4H), 3.04 (m, 5H), 2.87 (br s, 1H), 2.22 (m, 3H), 2.00 (m, 3H), 1.86 (m, 4H), 1.56 (m, 1H).

96B: Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline 31.0 mg (4% yield) as the HCl salt. MS (ESI): exact mass calcd for C₂₆H₃₄N₂O, 414.3; m/z found, 415.5 [M+H]⁺.

Example 97-(A-B)

97A: Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

97C: Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 5-(4-Bromo-phenyl)-3,4-dihydro-2H-pyrrole. Prepared as described in Example 39, Step 1, on a 93.0 mmol scale, to give 14.1 g (68%) of the desired product. MS (ESI): exact mass calcd for C₁₀H₁₀BrN, 223.0; m/z found, 224.0, 226.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.73 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 3.91 (2H), 2.86 (m, 2H), 1.91 (m, 2H).

Step 2. 2-(4-Bromo-phenyl)-pyrrolidine. Prepared as described in Example 39, Step 2, on a 87.2 mmol scale, to give 12.9 g (65%) of the desired product. MS (ESI): exact mass calcd for C₁₀H₁₂BrN, 225.0; m/z found, 226.1 [M+H]⁺, 228.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.44 (m, 2H), 7.30 (d, J=6.6 Hz, 2H), 3.99 (m, 1H), 2.96 (m, 1H), 2.88 (m, 1H), 2.31 (br s, 1H), 2.07 (m, 1H), 1.70 (m, 2H), 1.40 (m, 1H).

Step 3. 1-[2-(4-Bromo-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-methylsulfanyl-phenyl)-ethanone. A solution of 2-(4-bromo-phenyl)-pyrrolidine (16.8 mmol, 1.0 equiv.) and hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.0 equiv.) in xylenes (0.2 M) was heated at reflux for 3 d under nitrogen. The bulk of the xylenes was removed by distillation and the residue was purified by chromatography to give the desired product as a mixture of diastereomers (5.22 g, 77%). MS (ESI): exact mass calcd for C₁₉H₂₀BrNO₂S, 405.0; m/z found, 406.0 [M+H]⁺, 408.0 [M+H]⁺.

Step 4. Cis- and Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. A solution of amide from Step 3 (12.1 mmol) and polyphosphoric acid (5 g/g amide) was heated at 105° C. under nitrogen until the starting material was consumed (2 h). The reaction mixture was poured into water and extracted with CH₂Cl₂ (×2). The combined extracts were washed with satd. aq. NaHCO₃ and brine, dried (MgSO₄), and concentrated to provide the crude product. The diastereomers were separated by chromatographic purification (EtOAc/Hexanes).

Cis-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 1.39 g (30%). MS (ESI): exact mass calcd for C₁₉H₁₈BrNOS, 387.0; m/z found, 388.0 [M+H]⁺, 390.0 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.40 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.02 (m, 2H), 6.93 (d, J=8.2 Hz, 2H), 4.61 (s, 1H), 4.44 (m, 1H), 3.34 (m, 2H), 2.56 (m, 1H), 2.28 (s, 3H), 1.92 (m, 2H), 1.81 (m, 1H), 1.68 (m, 1H).

Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 849.4 mg (18%). MS (ESI): exact mass calcd for C₁₉H₁₈BrNOS, 387.0; m/z found, 388.0 [M+H]⁺, 390.0 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.36 (m, 1H), 7.21 (m, 3H), 7.07 (m, 2H), 6.60 (m, 1H), 4.62 (m, 1H), 3.49 (m, 1H), 3.37 (m, 1H), 2.66 (m, 1H), 2.44 (s, 3H), 1.97 (m, 4H).

Step 5. Cis- and Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. To a 0° C. solution of BH₃.THF (1 M in THF, 2.5 equiv.) was added a solution of cis-amino-ketone (Step 4, 3.45 mmol, 1 equiv.) in THF (2 M) and the resulting solution was heated at reflux for 1 h. The mixture was cooled to room temperature, quenched with water, and acidified with 12 N HCl. The THF was removed in vacuo and the aqueous mixture was heated at reflux for 15 min. The reaction mixture was again cooled to room temperature, made basic with 3 N NaOH, and extracted with CH₂Cl₂. The organic extract was washed with brine, dried (MgSO₄), and concentrated to give the crude products. A small portion of the crude product was purified by Gilson to give analytically pure products. The bulk of the material was carried forward without purification.

Cis-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 1.21 g (94%) as the TFA salt. MS (ESI): exact mass calcd for C₁₉H₂₀BrNS, 373.1; m/z found, 374.0 [M+H]⁺, 376.0 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄): 7.54 (d, J=8.0 Hz, 1H), 7.28 (m, 3H), 7.17 (br s, 1H), 7.09 (br s, 2H), 4.56 (br s, 1H), 3.70 (br m, 3H), 3.43 (br s, 1H), 2.76 (br s, 1H), 2.49 (s, 3H), 2.16 (br s, 3H).

Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. Prepared as described for the cis isomer, on a 0.856 mmol scale, to give 119.5 mg (37%) of the desired product as the TFA salt. MS (ESI): exact mass calcd for C₁₉H₂₀BrNS, 373.1; m/z found, 374.0 [M+H]⁺, 376.0 [M+H]⁺.

Step 6. Prepared on the cis-isomer from Step 5, as described in Example 33, on a 0.267 mmol scale. After the reaction was complete, the reaction mixture was diluted with diethyl ether, washed with water (×2), and filtered through a pad of diatomaceous earth. The filtrate was dried (Na₂CO₃) and concentrated to provide the crude product. Purification by reverse-phase HPLC afforded 22.1 mg (12%) of the desired product as the TFA salt.

97A: Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. MS (ESI): exact mass calcd for C₂₈H₃₄N₂S, 430.2; m/z found, 431.2 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄): 7.40 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.10 (br s, 2H), 7.02 (br s, 1H), 4.54 (br s, 1H), 3.74 (br s, 3H), 3.56 (d, J=12.1 Hz, 2H), 3.30 (m, 3H), 2.96 (m, 2H), 2.90 (m, 2H), 2.78 (br s, 1H), 2.47 (s, 3H), 2.15 (br s, 3H), 1.92 (d, J=14.6 Hz, 2H), 1.80 (m, 3H), 1.49 (m, 1H).

97B: Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. Prepared as described for the cis-isomer above, on a 0.0751 mmol scale, to give 34.4 mg (66%) of the desired product as the TFA salt. MS (ESI): exact mass calcd for C₂₈H₃₄N₂S, 430.2; m/z found, 431.2 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄): 7.33 (d, J=8.1 Hz, 1H), 7.29 (m, 3H), 7.17 (d, J=8.2 Hz, 2H), 6.79 (s, 1H), 4.36 (m, 1H), 3.86 (m, 1H), 3.44 (m, 5H), 3.26 (m, 3H), 2.90 (m, 5H), 2.47 (s, 3H), 2.25 (m, 3H), 1.87 (d, J=14.6 Hz, 2H), 1.68 (m, 3H), 1.44 (m, 1H).

Example 98-(A-B)

98A: Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

98B: Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline

Step 1. 1-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-methylsulfanyl-phenyl)-ethanone. A mixture of 2-(3-bromo-phenyl)-pyrrolidine (1.01 mmol, 1.0 equiv.), hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.05 equiv.), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.2 equiv.), and Hunig's base (1.5 equiv.) in CH₂Cl₂ (0.2 M) was stirred at room temperature overnight under nitrogen. The reaction mixture was filtered to remove a white precipitate and the filtrate was washed with 1 N HCl, water, 1 N NaOH, water, and brine, dried (MgSO₄), and concentrated to give the crude product as a mixture of diastereomers. The crude product was purified by normal phase column chromatography (EtOAc/hexanes) to give 220 mg (56%) of the desired product as a mixture of diastereomers. MS (ESI): exact mass calcd for C₁₉H₂₀BrNO₂S, 405.0; m/z found, 406.0, 408.0 [M+H]⁺.

Step 2. Prepared as described in Example 1, Step 7, on a 1.23 mmol scale. Purification by column chromatography (EtOAc/Hexanes) gave a 75% combined yield of two diastereomers, which were separated by reverse phase HPLC.

Cis-9-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 140 mg (29%) as the TFA salt. MS (ESI): exact mass calcd for C₁₉H₁₈BrNOS, 387.0; m/z found, 388.0, 390.0 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄): 7.48 (m, 1H), 7.30 (m, 3H), 7.11 (d, J=8.3 Hz, 2H), 6.47 (m, 1H), 4.76 (m, 1H), 4.73 (m, 1H), 3.68 (m, 1H), 3.51 (m, 1H), 2.77 (m, 1H), 2.49 (s, 3H), 2.20 (m, 1H), 2.12 (m, 1H), 2.10 (m, 1H).

Trans-9-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one. 220 mg (46%) as the TFA. MS (ESI): exact mass calcd for C₁₉H₁₈BrNOS, 387.0; m/z found, 387.9, 390.0 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄): 7.54 (s, 1H), 7.50 (m, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 4.79 (s, 1H), 4.63 (m, 1H), 3.55 (m, 2H), 2.71 (m, 1H), 2.41 (s, 3H), 2.12 (m, 1H), 1.99 (m, 1H), 1.86 (m, 1H).

Step 3. Performed as described in Example 97, Step 5, on a 7.7 mmol scale, to give a 78% combined yield of a 1:1 mixture of diastereomers. MS (ESI): exact mass calcd for C₁₉H₂₀BrNS, 374.3; m/z found, 374.0, 376.0 [M+H]⁺. The cis diastereomer was isolated by column chromatography and an analytical sample further purified by reverse phase HPLC.

Cis-9-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 1.13 g (39%) as the TFA salt. MS (ESI): exact mass calcd for C₁₉H₂₀BrNS, 373.1; m/z found, 374.0, 376.0 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.60 (m, 1H), 7.40 (m, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.23 (d, J=6.6 Hz, 2H), 7.98 (m, 1H), 4.59 (m, 1H), 3.96 (m, 1H), 3.71 (m, 2H), 3.50 (m, 1H), 3.41 (m, 1H), 2.95 (m, 1H), 2.49 (s, 3H), 2.37 (m, 2H), 2.28 (m, 1H).

Step 4. Prepared as described in Example 97, Step 6, on a 1.47 mmol scale, to give a 15% combined yield of a mixture of diastereomers. The diastereomers were isolated by reverse-phase HPLC.

98A: Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 45.0 mg (5%) as the TFA salt. MS (ESI): exact mass calcd for C₂₈H₃₄N₂S, 430.2; m/z found, 431.2 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.44 (s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 6.75 (d, J=8.1 Hz, 1H), 4.95 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 3.70 (m, 3H), 3.50 (m, 1H), 3.40 (m, 3H), 3.06 (m, 4H), 2.91 (m, 1H), 2.51 (s, 3H), 2.35 (m, 2H), 2.27 (m, 1H), 1.90 (m, 4H), 1.79 (m, 1H), 1.52 (m, 1H).

98B: Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline. 103 mg (11%) as the TFA salt. MS (ESI): exact mass calcd for C₂₈H₃₄N₂S, 430.2; m/z found, 431.2 [M+H]⁺. ¹H NMR (500 MHz, acetone-d₆): 7.47 (br s, 1H), 7.30 (m, 3H), 7.21 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.1 Hz, 1H), 5.13 (br s, 1H), 4.67 (br s, 1H), 3.70 (m, 5H), 3.43 (t, J=7.5 Hz, 2H), 3.07 (m, 4H), 2.79 (br s, 1H), 2.49 (s, 3H), 2.18 (m, 3H), 1.90 (m, H), 1.82 (m, 1H), 1.52 (m, 1H).

Biological Method 1. In Vitro Screening

H₃ Receptor Binding

Binding of compounds to the cloned human H₃ receptor, stably expressed in SK—N-MC cells, was performed (Lovenberg, T. W. et al. J. Pharmacol. Exp. Ther. 2000, 293, 771-778). Briefly, cell pellets from SK—N-MC cells expressing the human H₃ receptor were homogenized in 50 mM Tris-HCl/5 mM EDTA and re-centrifuged at 30,000 g for 30 min. Pellets were re-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were incubated with 0.8 nM N-[³H]-α-methylhistamine plus/minus test compounds for 60 min at 25° C. and harvested by rapid filtration over GF/C glass fiber filters (pretreated with 0.3% polyethylenimine) followed by four washes with ice-cold buffer. Nonspecific binding was defined in the presence of 10 μM histamine. IC₅₀ values were determined by a single site curve-fitting program (GraphPad, San Diego, Calif.) and converted to K_(i) values based on a N—[³H]-α-methylhistamine K_(d) of 800 pM and a ligand concentration of 800 pM (Cheng & Prusoff, Biochem. Pharmacol. 1973, 22, 3099-3108). Data for compounds testing in this assay are presented in Table 1.

Rat Brain SERT

A rat brain without cerebellum (Zivic Laboratories, Inc.—Pittsburgh, Pa.) was homogenized in a 52.6 mM Tris pH 8/126.4 mM NaCl/5.26 mM KCl mixture and centrifuged at 1,000 rpm for 5 min. The supernatant was removed and re-centrifuged at 15,000 rpm for 30 min. Pellets were re-homogenized in a 52.6 mM Tris pH8/126.4 mM NaCl/5.26 mM KCl mixture. Membranes were incubated with 0.6 nM [³H]-Citalopram plus/minus test compounds for 60 min at 25° C. and harvested by rapid filtration over GF/C glass fiber filters (pretreated with 0.3% polyethylenimine) followed by four washes with ice-cold buffer. Nonspecific binding was defined in the presence of 100 μM fluoxetine. IC₅₀ values were determined by a single site curve-fitting program (GraphPad, San Diego, Calif.) and converted to K_(i) values based on a [³H]-Citalopram K_(d) of 0.6 nM and a ligand concentration of 0.6 nM. Data for compounds tested in this assay are presented in Table 1.

TABLE 1 Rat SERT Human H₃ Rat SERT Human H₃ EX K_(i) (nM) K_(i) (nM) EX K_(i) (nM) K_(i) (nM)  1A 2 0.9 24B 36 0.3  1B 138 0.2 25 3 0.8  1C 4000 68 26 2 0.8  2A 5 1 27A 20 1  2B 544 31 27B 26 0.3  2C 4000 29 28 4 0.4  3 3 0.5 29 2 0.9  4A 15 1 30 3 2  4B 151 1 31 163 12  4C 471 98 32 20 1  4D 154 1 33 33 7  5A 3 2 34 9 2  5B 37 1 35A 15 4  5C 3000 85 35B 4 2  6A 1 3 36 15 4  6B 14 1 37 7 4  6C 291 76 38 10 6  7A 27 5 39A 3 2  7B 25 2 39B 3 1  7C 630 31 39C 69 36  8A 2 0.7 40 12 3  8B 50 0.75 41A 25 1  8C 2 2 41B 6 1  8D 3 1 42 221 2  8E 477 226 43 6000 30  8F 4000 482 44 4000 1  9A 9 2 45 6000 16  9B 6000 1000 46 14 4 10A 5 2 47 9 3 10B 37 2 48A 7 6 10C 2000 82 48B 20 5 11A 4 1 49 6 5 11B 91 1 50A 23 4 11C 1000 136 50B 363 181 12A 11 2 51A 130 3 12B 52 1 51B 161 5 12C 2000 91 52 6 4 12D 280 74 53 53 3 13A 14 1 54 24 4 13B 2000 129 55 39 2 14A 4 2 56 2 3 14B 67 1 57 3 3 14C 3000 200 58 8 2 15 1 0.7 59 4 2 16 21 4 60 8 3 17 11 4 61 10 29 18 12 0.9 62 15 6 19 12 1 63 5 16 20 21 1 64 3 3 21 7 1 65 4 4 22 64 0.8 66A 6 2 23 1 1 66B 18 1 24A 0.7 0.7 67 22 2 89 3 16 95 11 6 90 24 10 96A 10 1 91 60 64 97A 51 3 92 2.2 16 97B 407 12 93 13 5 98A 10 4 94 53 4 98B 7 3

Human SERT

Homogenized HEK293 (Human Embryonic Kidney) membranes expressing the human SERT (Perkin-Elmer) were incubated with ³H-citalopram (SERT) at rt for 1 h in 50 mM Tris, 120 mM NaCl, 5 mM KCl (pH 7.4). Nonspecific binding was determined in the presence of 10 μM fluoxetine for the SERT. The membranes were washed and the radioactivity was counted as above. Calculations for K_(i) at the SERT were based on a K_(d) value for ³H-citalopram and a ligand concentration of 3.1 nM. Data for compounds testing in this assay are presented in Table 2.

TABLE 2 Human SERT Human SERT Human SERT EX K_(i) (nM) EX K_(i) (nM) EX K_(i) (nM)  1A 4 15 3 29 2  2A 6 16 112 30 2  3 8 17 7 31 28  4A 4 18 13 32 11  5A 4 19 5 34 3  6A 4 20 43 35A 7  7A 12 21 5 37 0.8  8A 2 22 220 38 7  8B 128 23 2 39A 4  8C 1 24A 1 40 18  9A 58 25 18 41A 59 10A 2 26 6 46 9 11A 0.6 27A 15 47 5 12A 8 27B 112 66A 6 13A 21 28 5 67 9 14A 3 94 111 96A 9 92 4 95 13 97A 2000 98A 2

Cyclic AMP Accumulation

Sublines of SK-N-MC cells were created that expressed a reporter construct and the human H₃ receptor. The reporter gene (β-galactosidase) is under the control of multiple cyclic AMP responsive elements. In 96-well plates, histamine was added directly to the cell media followed 5 min later by an addition of forskolin (5 μM final concentration). When appropriate, antagonists were added 10 min prior to agonist addition. After a 6-h incubation at 37° C., the media was aspirated and the cells washed with 200 μL of phosphate-buffered saline followed by a second aspiration. Cells were lysed with 25 μL 0.1× assay buffer (10 mM Na-phosphate, pH 8, 0.2 mM MgSO₄, 0.01 mM MnCl₂) and incubated at rt for 10 min. Cells were then incubated for 10 min with 100 μL of 1× assay buffer containing 0.5% Triton and 40 mM β-mercaptoethanol. Color was developed using 25 μL of 1 mg/mL substrate solution (chlorophenolred β-D galactopyranoside; Roche Molecular Biochemicals, Indianapolis, Ind.). Color was quantitated on a microplate reader at absorbance 570 nM. The pA₂ values were calculated by Schild regression analysis of the pEC₅₀ values and are presented in Table 3.

TABLE 3 EX H₃ pA₂ EX H₃ pA₂ EX H₃ pA₂  1A 9.7 10A 9.8 23 9.7  1B 9.6 10B 9.6 24A 9.9  2A 9.4 11A 9.5 24B 10.0  2B 8.8 11B 9.3 25 10.0  3 10.1 12A 8.9 26 10.1  4A 9.9 12B 9.2 32 9.5  4B 9.8 14A 9.0 33 8.1  5A 8.6 14B 9.1 34 9.0  6A 8.2 15 9.9 35A 8.4  7A 8.2 16 8.9 35B 8.5  7B 8.2 17 8.2 36 8.0  8A 8.8 18 9.3 37 8.8  8B 9.2 19 9.4 41A 9.1  8C 8.8 20 9.0 41B 9.1  8D 8.8 21 9.1 67 9.3  9A 9.5 22 9.2 97B 8.0 91 8.5 96A 8.2 98A 8.0 92 7.8 97A 8.8 98B 8.6

Biological Method 2. In Vivo Screening.

Animal experiments were performed to illustrate that 6-(4-methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 8A) is both an H₃ receptor antagonist and a blocker of serotonin reuptake in vivo.

A. Imetit-Induced Drinking Model

Histamine H₃ receptors play an important role in the regulation of drinking behavior. For instance, it is known that administration of H₃ antagonists can decrease the drinking response to histamine by about 40% (Kraly, F. S. et al. Pharmacol., Biochem. Behav. 1996, 53, 347-354). Indeed, it is possible to induce drinking behavior in rodents by administering a selective agonist for the H₃ receptor, such as R-α-methylhistamine (Fox, G. B. et al. Pharmacol., Biochem. Behay. 2002b, 72, 741-750) or imetit.

The imetit-induced drinking model was used to provide evidence of in vivo antagonism of an H₃ mediated behavior. In this model, animals were introduced into a cage containing a fully-automated water drinking monitoring system. The animals were injected i.p. with Example 8A. After 24 h, 1 mg/kg imetit, which was shown during preliminary experiments to induce a robust drinking response, was administered i.p., and drinking was measured for a period of 60 min (imetit-induced drinking). Example 8A inhibited imetit-induced drinking with a statistically significant effect at 10 mg/kg i.p. Data are presented in Table 4. Results are shown as averages ±s.e.m. of n=8-13 animals.

TABLE 4 Treatment Water Consumed (mL) n Vehicle (saline) 1.05 ± 0.34 10 Imetit (1 mg/kg) 2.53 ± 0.60 13 Example 8A (1 mg/kg) + 1.99 ± 0.68 10 Imetit (1 mg/kg) Example 8A (3 mg/kg) + 1.65 ± 0.51 8 Imetit (1 mg/kg) Example 8A (10 mg/kg) + *0.25 ± 0.15  10 Imetit (1 mg/kg) *p = 0.022 compared to imetit-treated animals

B. 5-HTP Potentiation Test

The co-administration of the 5-HT precursor 5-HTP (5-hydroxytryptophan) and a decarboxylase inhibitor, carbidopa (Darmani, N. A. and S. L. Reeves. Pharmacol., Biochem. Behay. 1996, 55, 1-10) is known to induce a mild serotoninergic syndrome, mainly characterized by head twitches. In the presence of a compound blocking the synaptic reuptake of 5-HT, the syndrome will be potentiated.

Mice were injected with Example 8A (3 mg/kg and 10 mg/kg). Group 1 (1 h): 1) at t=0, mice were injected with carbidopa (10 mg/kg) and Example 8A (3 mg/kg or 10 mg/kg); 2) at t=20 min, mice were injected with 5-HTP (40 mg/kg); 3) at t=55 min, head twitch frequency was measured for a 5 min interval. Group 2 (24 h): 1) at t=0, mice were injected with Example 8A (3 mg/kg or 10 mg/kg); 2) at t=23 h, mice were injected with carbidopa (10 mg/kg); 3) at t=23 h, 20 min, mice were injected with 5-HTP (40 mg/kg); 4) at t=24 h, 25 min, head twitch frequency was measured for a 5 min interval. The data are presented in Table 5 as an average ±s.e.m. The n value is given between brackets.

TABLE 5 Group 1 (1 h) Group 2 (24 h) Vehicle 3.5 ± 0.6 (5)  6.2 ± 1.2 (4)  3 mg/kg Example 8A 6.0 ± 1.2 (3) 24.0 ± 2.1 (4) 10 mg/kg Example 8A 2.0 ± 0.6 (3) 41.3 ± 5.2 (3)

C. Microdialysis

Microdialysis is used to measure the concentration of small biological molecules in the extracellular fluid of the brain (Parent, M. et al. Methods 2001, 23, 11-20). A small probe, containing a fine microdialysis membrane at its tip, is introduced into the brain of an animal. A buffered solution is infused through the catheter. Small molecules, such as monoamine neurotransmitters, diffuse through the pores in the microdialysis membrane and are captured in the solution. The samples are then analyzed by analytical techniques to quantitate the amount of neurotransmitter in the brain extracellular fluid. This technique has been used extensively to measure the effects of SERT inhibitors on levels of extracellular serotonin.

Microdialysis was used to measure the levels of serotonin and dopamine in the brain of freely moving rats after subcutaneous injection of Example 8A. FIG. 1 shows the results of microdialysis of dopamine (DA) and serotonin (5-HT) in the cortex of freely moving rats after subcutaneous injection of 1 mg/kg of Example 8A at t=0. As shown in FIG. 1, injection of Example 8A caused a slow, persistent increase in serotonin and dopamine levels. Results are represented as the average ±s.d. of n=2-4 rats. 

1. A compound of formula (I):

wherein n is 0 or 1; m is 0; R² and R³ may be taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from >O, >S(O)₀₋₂, and >NH, having 0 or 1 double bonds, having 0, 1, or 2 carbon members separated from the nitrogen of attachment by at least one carbon member which is a carbonyl, optionally benzo or pyrido fused, optionally having one carbon member that forms a bridge, and having 0-1 substituents R^(ff), R^(ff) is selected from the group consisting of —C₁₋₆alkyl halo, and —C₁₋₆alkylOH R⁵ is selected from the group consisting of —H, —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, and halo; Ar¹ is a heteroaryl ring selected from the group consisting of: d) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C₁₋₄alkyl), having up to one additional carbon atom optionally replaced by —N═, optionally mono- or di-substituted with R^(t) R^(t) is a substituent independently selected from the group consisting of: —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl, —CN, —NO₂, —N(R^(u))R^(v) (wherein R^(u) and R^(v) are independently —H or —C₁₋₆alkyl), —C(O)N(R^(u))R^(v), —N(R^(u))C(O)R^(v), —N(R^(u))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(u))R^(v), —SCF₃, halo, —CF₃, —OCF₃, —OCHF₂, —COOH, and —COOC₁₋₆alkyl; e) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by —N═, optionally mono- or di-substituted with R^(t); and enantiomers, diastereomers, thereof, and pharmaceutically acceptable salts, esters and amides thereof.
 2. The compound of claim 1 wherein n is 0 or
 1. 3-6. (canceled)
 7. The compound of claim 1 wherein R² and R³, optionally substituted, are taken together with the nitrogen to which they are attached to form a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and 1,1-dioxo-1λ⁶-thiomorpholin-4-yl.
 8. The compound of claim 1 wherein R² and R³ are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocyclic ring, said heterocyclic ring selected from piperidine, pyrrolidine, and morpholine, said ring substituted with 1 substituent R^(ff).
 9. The compound of claim 1 wherein R^(ff) is selected from the group consisting of methyl, ethyl, isopropyl, butyl, hexyl, bromo, chloro, fluoro, iodo, hydroxymethyl, and hydroxyethyl.
 10. The compound of claim 1 wherein R^(ff) is selected from the group consisting of methyl, fluoro, and hydroxymethyl.
 11. (canceled)
 12. The compound of claim 1 wherein R² and R³ are taken together with the nitrogen to which they are attached to form azetidinyl, 2-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, morpholinyl, 2 hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl, 3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl, 1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl, or 2-methylmorpholin-4-yl.
 13. The compound of claim 1 wherein R² and R³ are taken together with the nitrogen to which they are attached to form 4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl. 14-18. (canceled)
 19. The compound of claim 1 wherein R⁵ is hydrogen, methyl, ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylsulfanyl, bromo, chloro, fluoro, or iodo.
 20. The compound of claim 1 wherein R⁵ is hydrogen.
 21. The compound of claim 1 wherein Ar¹, optionally substituted, is selected from the group consisting of: e) pyridinyl, pyridinyl-N-oxide, or pyrazinyl.
 22. The compound of claim 1 wherein Ar¹, optionally substituted, is selected from the group consisting of pyridyl, pyrazinyl, and thiophenyl.
 23. The compound of claim 1 wherein Ar¹ is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl, 2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl, 2-hydroxy-5-pyridinyl, and pyrazin-2-yl.
 24. (canceled)
 25. The compound of claim 1 wherein Ar¹ is cis to the pyrrolidine ring of formula (I).
 26. The compound of claim 1 wherein the R³R²N-containing ether substituent of formula (I) is at the 9-position.
 27. A compound selected from the group consisting of: Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Trans-9-(3-piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1 -a]isoquinoline; Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1 -a]isoquinoline; Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine; 6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; and 6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline.
 28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of formula (I). 29-45. (canceled) 